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Wu H, Gu J, He Y, Ji Y, Cao W, Li R, Gu Z, Wei G, Huo J. Exploring The Causal Relationship Between Lipid Profiles and Colorectal Cancer Through Mendelian Randomization: A Multidimensional Plasma Lipid Composition Perspective. J Cancer 2025; 16:1848-1859. [PMID: 40092699 PMCID: PMC11905406 DOI: 10.7150/jca.103247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 01/29/2025] [Indexed: 03/19/2025] Open
Abstract
Background: The causal relationship between blood lipids and colorectal cancer (CRC) risk has been preliminarily explored in previous Mendelian randomization (MR) studies, but these investigations were limited to conventional or partial metabolic lipid profiles. Recent advancements in genome-wide association studies of plasma lipidomics have expanded our understanding of lipid categories, underscoring the need to evaluate the causal associations between a broader range of lipid types and CRC risk to enhance risk assessment. Methods: This MR study utilized 179 lipid phenotypes across 13 lipid classes to investigate their causal associations with CRC risk. Genetic variants significantly associated with lipid traits at the genome-wide level (P<5×10-8) were used as instrumental variables for MR analysis. Initial analyses were conducted using a discovery dataset (n=321,040), followed by validation in an independent replication dataset (n=185,616). Meta-analysis was then employed to determine the strength of causal evidence. The inverse-variance weighted (IVW) method and Wald ratio were the primary MR approaches, complemented by up to nine methods for multidimensional validation. Sensitivity analyses included tests for pleiotropy, heterogeneity, Steiger directionality, and Bayesian colocalization analysis, among others. Results: After Bonferroni correction and rigorous validations, 9 significant causal associations were identified. Specifically, genetically predicted levels of sterol ester (27:1/20:5) (ORIVW = 1.214, 95% CI 1.119-1.317), phosphatidylcholine (20:4_0:0) (ORIVW = 1.147, 95% CI 1.077-1.222), phosphatidylcholine (16:0_22:4) (ORIVW = 1.312, 95% CI 1.170-1.472), phosphatidylcholine (16:0_22:5) (ORIVW =1.181, 95% CI 1.093-1.277), and phosphatidylcholine (18:0_20:5) (ORIVW = 1.198, 95% CI 1.104-1.300) were significantly associated with an increased risk of CRC. Conversely, levels of phosphatidylcholine (18:1_20:2) (ORIVW = 0.832, 95% CI 0.771-0.898), phosphatidylethanolamine (18:2_0:0) (ORIVW = 0.804, 95% CI 0.732-0.882), phosphatidylcholine (16:0_18:0) (ORWald ratio = 0.611, 95% CI 0.481-0.777), and phosphatidylcholine (O-18:1_18:2) (ORWald ratio = 0.723, 95% CI 0.620-0.840) were significantly associated with a decreased risk of CRC. Colocalization analysis revealed posterior probabilities for hypothesis 4 exceeding 90%, identifying rs174546 and rs28456 as shared causal variants. Additionally, 14 suggestive causal associations were observed. Conclusions: This study establishes a causal link between specific lipid species and CRC risk. These findings suggest new avenues for CRC prevention and treatment strategies.
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Affiliation(s)
- Hailan Wu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu, China
- Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu 210022, Jiangsu, China
| | - Jialin Gu
- Department of Traditional Chinese medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310013, Zhejiang, China
| | - Yun He
- Department of Oncology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu, China
| | - Yi Ji
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Wen Cao
- Jiangsu Cancer Hospital, Nanjing 210009, Jiangsu, China
| | - Rongrong Li
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Zhancheng Gu
- Department of Oncology, Kunshan Hospital of Traditional Chinese Medicine, Suzhou 215399, Jiangsu, China
| | - Guoli Wei
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Jiege Huo
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu, China
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Xiao Y, Du X, Wang T, Liu D, You H, Wang H, Liang H, Ba Z, Liu Y, Ren Y, Zeng J, Yang W, Wu S, Yuan J. Serum Lipid Biomarkers and the Risk of Gastrointestinal Cancers in a Chinese Population: The Kailuan Prospective Study. Cancer Med 2025; 14:e70654. [PMID: 39912426 PMCID: PMC11799922 DOI: 10.1002/cam4.70654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 12/25/2024] [Accepted: 01/25/2025] [Indexed: 02/07/2025] Open
Abstract
BACKGROUND Current evidence on relationships between serum lipid biomarkers and the risk of gastrointestinal cancers remains controversial, with no consensus reached. METHODS We conducted a prospective cohort study within the Kailuan Cohort wherein 88,225 individuals with baseline information on triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) was followed from 2006 to 2021 for the incidence of esophageal cancer (EC), gastric cancer (GC), and colorectal cancer (CRC). Cox proportional hazards models and restricted cubic spline (RCS) analysis were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS Increased EC risk was associated with high HDL-C levels (HRQ4vs.Q1 = 2.50, 95% CI: 1.57-3.98), while a U-shaped relationship between HDL-C and EC risk was revealed in the RCS analysis (poverall ≤ 0.0001, pnonlinear = 0.02). No robust association was identified between lipid biomarkers and GC risk. In multivariable analysis, increased CRC risk was positively associated with high TC levels (HRQ4vs.Q1 = 1.42, 95% CI: 1.11-1.83, ptrend = 0.03), dose-responsely negatively associated with LDL-C levels over quartiles (HRQ2vs.Q1 = 0.83, 95% CI: 0.66-1.02; HRQ3vs.Q1 = 0.86, 95% CI: 0.69-1.07; HRQ4vs.Q1 = 0.68, 95% CI: 0.53-0.86, ptrend = 0.02), and showed a diminished negative association with HDL-C levels over quartiles (HRQ2vs.Q1 = 0.75, 95% CI: 0.60-0.94; HRQ3vs.Q1 = 0.76, 95% CI: 0.61-0.95; HRQ4vs.Q1 = 0.91, 95% CI 0.74-1.13, ptrend = 0.02). The subsequent RCS analysis revealed a linear negative relationship of LDL-C (poverall = 0.004, pnonlinear = 0.67) and a U-shaped relationship of HDL-C (poverall = 0.05, pnonlinear = 0.02) with CRC risk. Competitive risk analysis and sensitivity analysis confirmed the stability of our results. CONCLUSION We observed a U-shaped relationship regarding HDL-C levels with EC and CRC risk, and a linear inverse relationship between LDL-C levels and CRC risk. Relevant serum lipid levels should be properly managed in high-risk individuals of certain gastrointestinal cancers.
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Affiliation(s)
- Ying Xiao
- Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular DiseasesBeijingChina
| | - Xin Du
- Department of CardiologyKailuan General HospitalTangshanChina
| | - Tianjie Wang
- Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular DiseasesBeijingChina
| | - Dong Liu
- Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular DiseasesBeijingChina
| | - Hongzhao You
- Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular DiseasesBeijingChina
| | - Hao Wang
- Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Hanyang Liang
- Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular DiseasesBeijingChina
| | - Zhengqing Ba
- Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular DiseasesBeijingChina
| | - Yilu Liu
- Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular DiseasesBeijingChina
| | - Yu Ren
- Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular DiseasesBeijingChina
| | - Jinghan Zeng
- Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular DiseasesBeijingChina
| | - Weixian Yang
- Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular DiseasesBeijingChina
| | - Shouling Wu
- Department of CardiologyKailuan General HospitalTangshanChina
| | - Jiansong Yuan
- Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular DiseasesBeijingChina
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Chan WC, Liu L, Bouras E, Zuber V, Wen W, Long J, Gill D, Murphy N, Gunter MJ, Assimes TL, Bujanda L, Gruber SB, Küry S, Lynch BM, Qu C, Thomas M, White E, Woods MO, Peters U, Li CI, Chan AT, Brenner H, Tsilidis KK, Zheng W. Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk: a Mendelian randomisation study. Br J Cancer 2025; 132:103-110. [PMID: 39580580 PMCID: PMC11723917 DOI: 10.1038/s41416-024-02900-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND Whether blood lipids are causally associated with colorectal cancer (CRC) risk remains unclear. METHODS Using two-sample Mendelian randomisation (MR), our study examined the associations of genetically-predicted blood concentrations of lipids and lipoproteins (primary: LDL-C, HDL-C, triglycerides, and total cholesterol), and genetically-proxied inhibition of HMGCR, NPC1L1, and PCSK9 (which mimic therapeutic effects of LDL-lowering drugs), with risks of CRC and its subsites. Genetic associations with lipids were obtained from the Global Lipids Genetics Consortium (n = 1,320,016), while genetic associations with CRC were obtained from the largest existing CRC consortium (n = 58,221 cases and 67,694 controls). Our main analysis was a multivariable MR (MVMR) with mutual adjustments for LDL-C, HDL-C, and triglycerides. Secondary analyses, including MVMR additionally-adjusting for BMI or diabetes, were also performed. RESULTS Genetically-predicted LDL-C was positively associated with CRC risk in the MVMR adjusted for HDL-C and triglycerides (OR = 1.09; 95%CI 1.02-1.16 per SD increase) and additionally-adjusted for BMI (OR = 1.12; 95%CI 1.05-1.21) or diabetes (OR = 1.09; 95%CI 1.02-1.17). Associations were generally consistent across anatomical subsites. No clear evidence of association was found for other lipids, lipoproteins, or LDL-lowering drug-targets. CONCLUSIONS We found evidence of a weak positive association between LDL-C and CRC that did not appear to be explained by potential pleiotropic pathways such as via HDL-C, triglycerides, BMI, or diabetes.
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Affiliation(s)
- Wing Ching Chan
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
| | - Lili Liu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Emmanouil Bouras
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Verena Zuber
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
- UK Dementia Research Institute at Imperial College, Imperial College London, London, UK
| | - Wanqing Wen
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jirong Long
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Marc J Gunter
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Themistocles L Assimes
- VA Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Luis Bujanda
- Department of Gastroenterology, Biodonostia Health Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain
| | - Stephen B Gruber
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
| | - Sébastien Küry
- Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France
| | - Brigid M Lynch
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Conghui Qu
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Minta Thomas
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Emily White
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Michael O Woods
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL, Canada
| | - Ulrike Peters
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Christopher I Li
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Konstantinos K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
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Zhang Z, Wu Z, Zeng Y, Li Y, Feng Y, Gao Z, Chen Y. Association of Methylenetetrahydrofolate Reductase Gene rs1801133 Polymorphism and Controlling Nutritional Status (CONUT) Score with Colorectal Cancer Susceptibility. Int J Gen Med 2024; 17:6281-6290. [PMID: 39712200 PMCID: PMC11662921 DOI: 10.2147/ijgm.s495139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 12/13/2024] [Indexed: 12/24/2024] Open
Abstract
Background Susceptibility to some cancers is linked to methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the Controlling Nutritional Status (CONUT) score in some populations. However, their relationship with susceptibility to colorectal cancer (CRC) susceptibility in the Hakka Chinese population remains unclear. Methods In total, 620 CRC patients and 734 controls were enrolled. MTHFR rs1801133 was genotyped, medical records (age, sex, smoking history, alcohol consumption, hypertension, diabetes mellitus, and family history of cancer, and blood cell parameters) were collected, and the relationship between this information and CRC susceptibility was analyzed. Results There were significant differences in the distribution of CONUT classification (p=0.002), and proportions of history of smoking (p<0.001), hypertension (p<0.001), diabetes mellitus (p<0.001), and family history of cancer (p=0.002) between patients and controls. There were statistically significant differences in MTHFR rs1801133 genotypes distribution (58.7% C/C, 35.5% C/T, and 5.8% T/T in patients vs 65.5%, 31.2%, and 3.3% in controls, p=0.010) and allele distribution (76.5% C, and 23.5% T allele in patients vs 81.1%, and 18.9% in controls, p=0.003) between patients and controls. Logistic regression analysis indicated that non-normal CONUT range (non-normal vs normal, odds ratio (OR): 1.451, 95% confidence interval (CI): 1.119-1.882, p=0.005), and MTHFR rs1801133 variant (C/T + T/T vs C/C, OR: 1.373, 95% CI: 1.091-1.728, p=0.007), older age (≥65 vs <65 years, OR: 1.298, 95% CI: 1.023-1.646, p=0.032), male sex (OR: 1.354, 95% CI: 1.067-1.718, p=0.013), and history of alcohol drinking (OR: 2.232, 95% CI: 1.164-4.282, p=0.016) were independently associated with CRC risk. Conclusion Individuals carried MTHFR rs1801133 variant and with non-normal CONUT range, advanced age, history of alcohol consumption may be at increased CRC risk in the Hakka population.
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Affiliation(s)
- Zhuoxin Zhang
- Department of Gastrointestinal Surgery, Meizhou People’s Hospital, Meizhou, People’s Republic of China
| | - Zuguang Wu
- Department of Gastrointestinal Surgery, Meizhou People’s Hospital, Meizhou, People’s Republic of China
| | - Yuwen Zeng
- Department of Gastrointestinal Surgery, Meizhou People’s Hospital, Meizhou, People’s Republic of China
| | - Yunlin Li
- Department of Gastrointestinal Surgery, Meizhou People’s Hospital, Meizhou, People’s Republic of China
| | - Yingchuan Feng
- Department of Gastrointestinal Surgery, Meizhou People’s Hospital, Meizhou, People’s Republic of China
| | - Zhen Gao
- Department of Gastrointestinal Surgery, Meizhou People’s Hospital, Meizhou, People’s Republic of China
| | - Yijin Chen
- Department of Gastroenterology, Meizhou People’s Hospital, Meizhou, People’s Republic of China
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Huang YX, Wu JH, Zhao YQ, Sui WN, Tian T, Han WX, Ni J. An atlas on risk factors for gastrointestinal cancers: A systematic review of Mendelian randomization studies. Prev Med 2024; 189:108147. [PMID: 39368643 DOI: 10.1016/j.ypmed.2024.108147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 09/27/2024] [Accepted: 09/28/2024] [Indexed: 10/07/2024]
Abstract
OBJECTIVE Gastrointestinal cancers are one of the most frequent cancer types and seriously threaten human life and health. Recent studies attribute the occurrence of gastrointestinal cancers to both genetic and environmental factors, yet the intrinsic etiology remains unclear. Mendelian randomization is a powerful well-established statistical method that is based on genome-wide association study (GWAS) to evaluate the causal relationship between exposures and outcomes. In the present study, we aimed to conduct a systematic review of Mendelian randomization studies investigating any causal risk factors for gastrointestinal cancers. METHODS We systematically searched Mendelian randomization studies that addressed the associations of genetically predicted exposures with five main gastrointestinal cancers from September 2014 to March 2024, as well as testing the research quality and validity. RESULTS Our findings suggested robust and consistent causal effects of body mass index (BMI), basal metabolic rate, fatty acids, total cholesterol, total bilirubin, insulin like growth factor-1, eosinophil counts, interleukin 2, alcohol consumption, coffee consumption, apolipoprotein B on colorectal cancer risks, BMI, waist circumference, low-density lipoprotein (LDL), total testosterone, smoking on gastric cancer risks, BMI, fasting insulin, LDL, waist circumference, visceral adipose tissue (VAT), immune cells, type 2 diabetes mellitus (T2DM) on pancreatic cancer risks, waist circumference, smoking, T2DM on esophageal adenocarcinoma risks, and VAT, ferritin, transferrin, alcohol consumption, hepatitis B virus infection, rheumatoid arthritis on liver cancer risks, respectively. CONCLUSION Larger, well-designed Mendelian randomization studies are practical in determining the causal status of risk factors for diseases.
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Affiliation(s)
- Yi-Xuan Huang
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Jun-Hua Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Yu-Qiang Zhao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Wan-Nian Sui
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Tian Tian
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Wen-Xiu Han
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
| | - Jing Ni
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.
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Zhou L, Zhang J. Immune cells mediate the causal relationship between uveitis and colorectal cancer via Mendelian randomization analysis. Sci Rep 2024; 14:25964. [PMID: 39472473 PMCID: PMC11522305 DOI: 10.1038/s41598-024-77758-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 10/24/2024] [Indexed: 11/02/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most common and deadly malignancies worldwide, and immune regulation plays a critical role in its development. This study investigates the causal relationships between uveitis, specific immune cell traits, and CRC using Mendelian Randomization (MR) analyses. A total of 21 single nucleotide polymorphisms (SNPs) associated with uveitis were identified, and the analysis revealed that a 1 log-odds increase in uveitis was linked to a statistically significant 3.0% reduction in CRC odds (IVW OR = 0.970, 95% CI: 0.946-0.995, P = 0.021). This protective effect was also observed using the weighted median approach (OR = 0.963, 95% CI: 0.931-0.997, P = 0.034), reinforcing the robustness of the findings. Furthermore, both univariable and multivariable MR analyses highlighted the significant causal influence of specific immune cell traits on CRC odds. Notably, the levels of extracellular monocyte HLA-DR expression emerged as a critical factor, with an associated increase in CRC odds (IVW OR = 1.084, 95% CI: 1.008-1.165, P = 0.030). The proportion of CRC odds mediated by the levels of extracellular monocyte HLA-DR expression, calculated as the ratio of the indirect effect to the total effect using estimates from multivariable MR analyses, was approximately 34.1%(95% CI: 10.23-58.04%). These findings underscore the complex interplay between immune regulation and carcinogenesis, offering insights into potential mechanisms underlying CRC development and suggesting avenues for targeted prevention and therapeutic strategies.
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Affiliation(s)
- Li Zhou
- Department of Anesthesiology, The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing, 402160, China
| | - Jiwang Zhang
- Department of Clinical Laboratory, The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing, 402160, China.
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Huang C, Liang W, Sun Y. The role of BMI, serum lipid profile molecules and their derivative indexes in colorectal polyps. ADVANCES IN LABORATORY MEDICINE 2024; 5:276-282. [PMID: 39252808 PMCID: PMC11381085 DOI: 10.1515/almed-2023-0170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/16/2024] [Indexed: 09/11/2024]
Abstract
Objectives To investigate the role of body mass index (BMI), serum lipid profile molecules and their derivative indexes in colorectal polyps. Methods A total of 352 individuals who underwent colonoscopy at our center were included in this retrospective analysis. Of these, 247 patients without evident abnormalities (control group), while 105 patients diagnosed with colorectal polyps (patient group). Serum lipid profile molecules and their derivative indexes were then compared between the two groups. Results The patient group exhibited significantly higher levels of total cholesterol (TC) and apolipoprotein B (ApoB) compared to the control group (p<0.05). In males, the patient group displayed elevated levels of ApoB and ApoB/ApoA1 ratio compared to the control group (p<0.05). Additionally, the triglycerides (TG) and TG/high-density lipoprotein-cholesterol (HDL-C) ratios were significantly higher in the multiple polyps group than in the single polyp group (p<0.05). Furthermore, the HDL-C and HDL-C/ApoA1 ratio levels were higher in the adenomatous polyp group when compared to the non-adenomatous polyp group (p<0.05). Multiple logistic regression analysis indicated that total cholesterol (TC), TG, low-density lipoprotein-cholesterol (LDL-C), TC/HDL-C ratio, TG/HDL-C ratio and LDL-C/HDL-C ratio were risk factors for the occurrence of colorectal polyps (p<0.05). ROC curve analyses revealed that TC, ApoB, and ApoB/ApoA1 ratio were associated with colorectal polyps. No significant difference in BMI between the two groups (p>0.05). Conclusions The incidence and progression of colorectal polyps are linked to serum lipid molecules and their derivative indexes. Dyslipidemia may increase the risk of colorectal polyps, potentially leading to colorectal cancer (CRC).
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Affiliation(s)
- Chunyu Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Department of Endoscopy, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Weipeng Liang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Yuying Sun
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
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8
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Huang C, Liang W, Sun Y. El papel del IMC, las moléculas del perfil lipídico sérico y sus índices derivados en los pólipos colorrectales. ADVANCES IN LABORATORY MEDICINE 2024; 5:283-290. [PMID: 39252798 PMCID: PMC11381628 DOI: 10.1515/almed-2024-0060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/16/2024] [Indexed: 09/11/2024]
Abstract
Resumen
Objetivos
Investigar el papel del IMC, las moléculas del perfil lipídico en suero y los cocientes lipoproteicos en los pólipos colorrectales.
Métodos
En un análisis retrospectivo, se incluyó a 352 sujetos sometidos a una colonoscopia en nuestro centro, de los cuales 247 no mostraron ninguna alteración evidente (grupo control), mientras que 105 recibieron un diagnóstico de uno o múltiples pólipos (grupo de pacientes). Se compararon las moléculas del perfil lipídico sérico y los cocientes lipoproteicos de los dos grupos.
Resultados
El grupo de pacientes mostró niveles significativamente mayores de colesterol total (CT) y apolipoproteína B (ApoB) que el grupo de control (p<0,05). Entre los hombres, el grupo de pacientes mostró niveles de ApoB y una relación ApoB/ApoA1 superiores a los del grupo de control (p<0,05). Así mismo, los niveles de triglicéridos (TG) y la relación TG/C-HDL (colesterol de lipoproteínas de alta densidad) fueron significativamente más elevados en el grupo de pólipos múltiples que en el de un solo pólipo (p<0,05). Además, los niveles de C-HDL y la relación C-HDL/ApoA1 fueron más altos en el grupo con pólipos adenomatosos que en el de no adenomatosos (p<0,05). El análisis de regresión logística múltiple identificó al CT, TG, LDL-C y a los cocientes CT/C-HDL, TG/C-HDL y C-LDL/C-HDL como factores de riesgo para el desarrollo de pólipos colorrectales (p<0,05). Los análisis de la curva ROC revelaron una asociación entre el CT, la ApoB, y la relación ApoB/ApoA1 y los pólipos colorrectales. Por otro lado, no se observaron diferencias estadísticamente significativas en el IMC entre los dos grupos (p>0,05).
Conclusiones
La incidencia y evolución de los pólipos colorrectales están relacionados con las moléculas del perfil lipídico en suero y los cocientes lipoproteicos de las mismas. La dislipidemia podría incrementar el riesgo de desarrollar pólipos colorrectales, pudiendo derivar posteriormente en el desarrollo de cáncer colorrectal (CRC).
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Affiliation(s)
- Chunyu Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Servicio de Endoscopias, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Weipeng Liang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yuying Sun
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, China
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9
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Peruchet-Noray L, Sedlmeier AM, Dimou N, Baurecht H, Fervers B, Fontvieille E, Konzok J, Tsilidis KK, Christakoudi S, Jansana A, Cordova R, Bohmann P, Stein MJ, Weber A, Bézieau S, Brenner H, Chan AT, Cheng I, Figueiredo JC, Garcia-Etxebarria K, Moreno V, Newton CC, Schmit SL, Song M, Ulrich CM, Ferrari P, Viallon V, Carreras-Torres R, Gunter MJ, Freisling H. Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer. SCIENCE ADVANCES 2024; 10:eadj1987. [PMID: 38640244 PMCID: PMC11029802 DOI: 10.1126/sciadv.adj1987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 03/12/2024] [Indexed: 04/21/2024]
Abstract
It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue-specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue-specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.
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Affiliation(s)
- Laia Peruchet-Noray
- International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, 69366 Lyon CEDEX 07, France
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Anja M. Sedlmeier
- Center for Translational Oncology, University Hospital Regensburg, Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), Regensburg, Germany
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
| | - Niki Dimou
- International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, 69366 Lyon CEDEX 07, France
| | - Hansjörg Baurecht
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
| | - Béatrice Fervers
- Département Prévention Cancer Environnement, Centre Léon Bérard, Lyon, France
| | - Emma Fontvieille
- International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, 69366 Lyon CEDEX 07, France
| | - Julian Konzok
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
| | - Kostas K. Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, Norfolk Place, London W2 1PG, UK
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Sofia Christakoudi
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, Norfolk Place, London W2 1PG, UK
- Department of Inflammation Biology, School of Immunology & Microbial Sciences, King’s College London, London, UK
| | - Anna Jansana
- International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, 69366 Lyon CEDEX 07, France
| | - Reynalda Cordova
- International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, 69366 Lyon CEDEX 07, France
- Department of Nutritional Sciences, University of Vienna, Vienna, Austria
| | - Patricia Bohmann
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
| | - Michael J. Stein
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
| | - Andrea Weber
- Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
| | - Stéphane Bézieau
- Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andrew T. Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Iona Cheng
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Jane C. Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Koldo Garcia-Etxebarria
- Biodonostia, Gastrointestinal Genetics Group, San Sebastián, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Victor Moreno
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
| | | | - Stephanie L. Schmit
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
- Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Departments of Epidemiology and Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - Cornelia M. Ulrich
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Pietro Ferrari
- International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, 69366 Lyon CEDEX 07, France
| | - Vivian Viallon
- International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, 69366 Lyon CEDEX 07, France
| | - Robert Carreras-Torres
- Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, Girona, Spain
| | - Marc J. Gunter
- International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, 69366 Lyon CEDEX 07, France
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, Norfolk Place, London W2 1PG, UK
| | - Heinz Freisling
- International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, 69366 Lyon CEDEX 07, France
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10
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Ruan X, Che T, Chen X, Sun Y, Fu T, Yuan S, Li X, Chen J, Wang X. Mendelian randomisation analysis for intestinal disease: achievement and future. EGASTROENTEROLOGY 2024; 2:e100058. [PMID: 39944470 PMCID: PMC11770446 DOI: 10.1136/egastro-2023-100058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 05/29/2024] [Indexed: 01/04/2025]
Abstract
Intestinal disease is a group of complex digestive system diseases imposing a significant burden globally. Identifying the risk factors and potential complications of intestinal disease is important for its prevention and treatment. However, traditional observational clinical studies are limited by confounding factors and reverse causation, making causal inference challenging. Mendelian randomisation (MR) method has been developed to effectively mitigate these constraints and assess the causal relationships. This review briefly introduces the MR method, summarises MR research on intestinal disease and delineates the prospective avenues for future research. Conventional risk factors, such as lifestyle behaviours (eg, physical activity, smoking and alcohol consumption), nutrients (eg, selenium), obesity markers (eg, body mass index and waist-to-hip ratio) and inflammatory biomarkers, have been validated in MR studies. Multiomics MR studies are becoming novel hotspots, which provide a theoretical foundation for the exploration of pathogenesis and the investigation of new drug targets. However, most of the recent studies are based on European individuals, and thus it is necessary to replicate the results in other ancestries. Moreover, triangulation integrating MR and other epidemiology methods is suggested as a validated paradigm for causal inference in future MR studies.
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Affiliation(s)
- Xixian Ruan
- Department of Gastroenterology, Central South University Third Xiangya Hospital, Changsha, Hunan, China
| | - Tianyi Che
- Department of Gastroenterology, Shanghai Jiao Tong University, Shanghai, China
| | - Xuejie Chen
- Department of Gastroenterology, Central South University Third Xiangya Hospital, Changsha, Hunan, China
| | - Yuhao Sun
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Tian Fu
- Department of Gastroenterology, Central South University Third Xiangya Hospital, Changsha, Hunan, China
| | - Shuai Yuan
- Karolinska Institutet, Stockholm, Sweden
| | - Xue Li
- Department of Big Data in Health Science, Center of Clinical Big Data, Zhejiang University School of Medicine, Hangzhou, China
| | - Jie Chen
- Department of Gastroenterology, Central South University Third Xiangya Hospital, Changsha, Hunan, China
- Centre for Global Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoyan Wang
- Department of Gastroenterology, Central South University Third Xiangya Hospital, Changsha, Hunan, China
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11
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Harewood R, Rothwell JA, Bešević J, Viallon V, Achaintre D, Gicquiau A, Rinaldi S, Wedekind R, Prehn C, Adamski J, Schmidt JA, Jacobs I, Tjønneland A, Olsen A, Severi G, Kaaks R, Katzke V, Schulze MB, Prada M, Masala G, Agnoli C, Panico S, Sacerdote C, Jakszyn PG, Sánchez MJ, Castilla J, Chirlaque MD, Atxega AA, van Guelpen B, Heath AK, Papier K, Tong TYN, Summers SA, Playdon M, Cross AJ, Keski-Rahkonen P, Chajès V, Murphy N, Gunter MJ. Association between pre-diagnostic circulating lipid metabolites and colorectal cancer risk: a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). EBioMedicine 2024; 101:105024. [PMID: 38412638 PMCID: PMC10907191 DOI: 10.1016/j.ebiom.2024.105024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 01/26/2024] [Accepted: 02/05/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Altered lipid metabolism is a hallmark of cancer development. However, the role of specific lipid metabolites in colorectal cancer development is uncertain. METHODS In a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined associations between pre-diagnostic circulating concentrations of 97 lipid metabolites (acylcarnitines, glycerophospholipids and sphingolipids) and colorectal cancer risk. Circulating lipids were measured using targeted mass spectrometry in 1591 incident colorectal cancer cases (55% women) and 1591 matched controls. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between concentrations of individual lipid metabolites and metabolite patterns with colorectal cancer risk. FINDINGS Of the 97 assayed lipids, 24 were inversely associated (nominally p < 0.05) with colorectal cancer risk. Hydroxysphingomyelin (SM (OH)) C22:2 (ORper doubling 0.60, 95% CI 0.47-0.77) and acylakyl-phosphatidylcholine (PC ae) C34:3 (ORper doubling 0.71, 95% CI 0.59-0.87) remained associated after multiple comparisons correction. These associations were unaltered after excluding the first 5 years of follow-up after blood collection and were consistent according to sex, age at diagnosis, BMI, and colorectal subsite. Two lipid patterns, one including 26 phosphatidylcholines and all sphingolipids, and another 30 phosphatidylcholines, were weakly inversely associated with colorectal cancer. INTERPRETATION Elevated pre-diagnostic circulating levels of SM (OH) C22:2 and PC ae C34:3 and lipid patterns including phosphatidylcholines and sphingolipids were associated with lower colorectal cancer risk. This study may provide insight into potential links between specific lipids and colorectal cancer development. Additional prospective studies are needed to validate the observed associations. FUNDING World Cancer Research Fund (reference: 2013/1002); European Commission (FP7: BBMRI-LPC; reference: 313010).
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Affiliation(s)
- Rhea Harewood
- International Agency for Research on Cancer (IARC), 25 Av. Tony Garnier, 69007, Lyon, France.
| | - Joseph A Rothwell
- Centre for Epidemiology and Population Health (U1018), Exposome and Heredity Team, Faculté de Médecine, Université Paris-Saclay, UVSQ, INSERM, Gustave Roussy, F-94805, Villejuif, France
| | - Jelena Bešević
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Vivian Viallon
- International Agency for Research on Cancer (IARC), 25 Av. Tony Garnier, 69007, Lyon, France
| | - David Achaintre
- International Agency for Research on Cancer (IARC), 25 Av. Tony Garnier, 69007, Lyon, France; School of Plant Sciences and Food Security, Faculty of Biology, Tel-Aviv University, Tel Aviv-Yafo, Israel
| | - Audrey Gicquiau
- International Agency for Research on Cancer (IARC), 25 Av. Tony Garnier, 69007, Lyon, France
| | - Sabina Rinaldi
- International Agency for Research on Cancer (IARC), 25 Av. Tony Garnier, 69007, Lyon, France
| | - Roland Wedekind
- International Agency for Research on Cancer (IARC), 25 Av. Tony Garnier, 69007, Lyon, France
| | - Cornelia Prehn
- Metabolomics and Proteomics Core, Helmholtz Zentrum München, 85764, Neuherberg, Germany
| | - Jerzy Adamski
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore, 117597; Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany; Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000, Ljubljana, Slovenia
| | - Julie A Schmidt
- Department of Clinical Medicine, Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark
| | - Inarie Jacobs
- International Agency for Research on Cancer (IARC), 25 Av. Tony Garnier, 69007, Lyon, France
| | - Anne Tjønneland
- Danish Cancer Society Research Center, Diet, Cancer and Health, Strandboulevarden 49, DK-2100, Copenhagen, Denmark; Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Anja Olsen
- Danish Cancer Society Research Center, Diet, Cancer and Health, Strandboulevarden 49, DK-2100, Copenhagen, Denmark; The Department of Public Health, University of Aarhus, Aarhus, Denmark
| | - Gianluca Severi
- Centre for Epidemiology and Population Health (U1018), Exposome and Heredity Team, Faculté de Médecine, Université Paris-Saclay, UVSQ, INSERM, Gustave Roussy, F-94805, Villejuif, France; Department of Statistics, Computer Science, Applications "G. Parenti", University of Florence, Florence, Italy
| | - Rudolf Kaaks
- German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany
| | - Verena Katzke
- German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany
| | - Matthias B Schulze
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Marcela Prada
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Giovanna Masala
- Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
| | - Claudia Agnoli
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy
| | - Salvatore Panico
- Dipartimento Di Medicina Clinica E Chirurgia Federico Ii University, Naples, Italy
| | - Carlotta Sacerdote
- Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Via Santena 7, 10126, Turin, Italy
| | - Paula Gabriela Jakszyn
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain; Blanquerna School of Health Sciences, Ramon Llull University, Barcelona, Spain
| | - Maria-Jose Sánchez
- Escuela Andaluza de Salud Pública (EASP), 18011, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, Granada, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029, Madrid, Spain; Department of Preventive Medicine and Public Health, University of Granada, 18071, Granada, Spain
| | - Jesús Castilla
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029, Madrid, Spain; Instituto de Salud Pública de Navarra - IdiSNA, Pamplona, Spain
| | - María-Dolores Chirlaque
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029, Madrid, Spain; Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain
| | - Amaia Aizpurua Atxega
- Ministry of Health of the Basque Government, Sub Directorate for Public Health and Addictions of Gipuzkoa, San Sebastian, Spain; Biodonostia Health Research Institute, Epidemiology of Chronic and Communicable Diseases Group, San Sebastián, Spain
| | - Bethany van Guelpen
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Alicia K Heath
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Keren Papier
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Tammy Y N Tong
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, Utah, USA
| | - Mary Playdon
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, Utah, USA; Cancer Control and Population Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Pekka Keski-Rahkonen
- International Agency for Research on Cancer (IARC), 25 Av. Tony Garnier, 69007, Lyon, France
| | - Véronique Chajès
- International Agency for Research on Cancer (IARC), 25 Av. Tony Garnier, 69007, Lyon, France
| | - Neil Murphy
- International Agency for Research on Cancer (IARC), 25 Av. Tony Garnier, 69007, Lyon, France
| | - Marc J Gunter
- International Agency for Research on Cancer (IARC), 25 Av. Tony Garnier, 69007, Lyon, France; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
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12
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Allegra A, Murdaca G, Mirabile G, Gangemi S. Protective Effects of High-Density Lipoprotein on Cancer Risk: Focus on Multiple Myeloma. Biomedicines 2024; 12:514. [PMID: 38540127 PMCID: PMC10967848 DOI: 10.3390/biomedicines12030514] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 04/03/2025] Open
Abstract
Lipid metabolism is intrinsically linked to tumorigenesis. And one of the most important characteristics of cancer is the modification of lipid metabolism and its correlation with oncogenic signaling pathways within the tumors. Because lipids function as signaling molecules, membrane structures, and energy sources, lipids are essential to the development of cancer. Above all, the proper immune response of tumor cells depends on the control of lipid metabolism. Changes in metabolism can modify systems that regulate carcinogenesis, such as inflammation, oxidative stress, and angiogenesis. The dependence of various malignancies on lipid metabolism varies. This review delves into the modifications to lipid metabolism that take place in cancer, specifically focusing on multiple myeloma. The review illustrates how changes in different lipid pathways impact the growth, survival, and drug-responsiveness of multiple myeloma cells, in addition to their interactions with other cells within the tumor microenvironment. The phenotype of malignant plasma cells can be affected by lipid vulnerabilities, and these findings offer a new avenue for understanding this process. Additionally, they identify novel druggable pathways that have a major bearing on multiple myeloma care.
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Affiliation(s)
- Alessandro Allegra
- Hematology Unit, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (A.A.); (G.M.)
| | - Giuseppe Murdaca
- Department of Internal Medicine, University of Genova, Viale Benedetto XV, 16132 Genova, Italy
- Allergology and Clinical Immunology Unit, San Bartolomeo Hospital, 19038 Sarzana, Italy
| | - Giuseppe Mirabile
- Hematology Unit, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (A.A.); (G.M.)
| | - Sebastiano Gangemi
- Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy;
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13
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Chen Y, Kong W, Liu M, Li Q, Wang Y, Zheng Y, Zhou Y. Metabolic syndrome and risk of colorectal cancer: A Mendelian randomization study. Heliyon 2024; 10:e23872. [PMID: 38223733 PMCID: PMC10784169 DOI: 10.1016/j.heliyon.2023.e23872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 12/01/2023] [Accepted: 12/14/2023] [Indexed: 01/16/2024] Open
Abstract
Background Observational studies have previously demonstrated a significant relationship among both metabolic syndrome (Mets) and colorectal cancer (CRC). Whether there is a causal link remains controversial. Objective To clarify whether Mets and their components have a causal effect on colorectal cancer, we have carried out a bidirectional Mendelian randomization analysis (MR). Methods This study started from genome-wide association data for Mets and its 5 components (hypertension, waist circumference, fasting blood glucose, serum triglycerides, and serum high-density lipoprotein cholesterol) and colorectal cancer. Mendelian randomization (MR) techniques were used in the study to examine their associations. Results After Benjamini-Hochberg multiple corrections, genetically predicted significant causal link exists between WC (waist circumference) and CRC. The OR was 1.35 (95 % CI: 1.08-1.69; p = 0.0096). Other Mets components (HBP, FBG, TG, HDL), on the other hand, found no evidence of a genetic link between CRC and Mets. In addition, MR results showed that CRC was not causally related to either Mets or the components. We get the same result in the validated dataset. Conclusion According to the bidirectional MR investigation shows a significant causal relationship among obesity and CRC in the Mets component but no causal relationship in the opposite direction.
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Affiliation(s)
- Yuhua Chen
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Wanru Kong
- Department of Infection Management, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - Min Liu
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Qiang Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yuping Wang
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ya Zheng
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yongning Zhou
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
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Bull C, Hazelwood E, Bell JA, Tan V, Constantinescu AE, Borges C, Legge D, Burrows K, Huyghe JR, Brenner H, Castellvi-Bel S, Chan AT, Kweon SS, Le Marchand L, Li L, Cheng I, Pai RK, Figueiredo JC, Murphy N, Gunter MJ, Timpson NJ, Vincent EE. Identifying metabolic features of colorectal cancer liability using Mendelian randomization. eLife 2023; 12:RP87894. [PMID: 38127078 PMCID: PMC10735227 DOI: 10.7554/elife.87894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023] Open
Abstract
Background Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. Methods To investigate whether changes in circulating metabolites characterize the early stages of colorectal cancer (CRC) development, we examined the associations between a genetic risk score (GRS) associated with CRC liability (72 single-nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N = 6221). Linear regression models were applied to examine the associations between genetic liability to CRC and circulating metabolites measured in the same individuals at age 8 y, 16 y, 18 y, and 25 y. Results The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P < 0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N = 118,466, median age 58 y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk. Conclusions These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism and suggest that fatty acids may play an important role in CRC development. Funding This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.
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Affiliation(s)
- Caroline Bull
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
- Translational Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Emma Hazelwood
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Joshua A Bell
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Vanessa Tan
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Andrei-Emil Constantinescu
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Carolina Borges
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Danny Legge
- Translational Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Kimberley Burrows
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer CenterSeattleUnited States
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)HeidelbergGermany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)HeidelbergGermany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
| | - Sergi Castellvi-Bel
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of BarcelonaBarcelonaSpain
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical SchoolBostonUnited States
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical SchoolBostonUnited States
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical SchoolBostonUnited States
- Broad Institute of Harvard and MITCambridgeUnited States
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard UniversityBostonUnited States
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard UniversityBostonUnited States
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical SchoolGwangjuRepublic of Korea
- Jeonnam Regional Cancer Center, Chonnam National University Hwasun HospitalHwasunRepublic of Korea
| | | | - Li Li
- Department of Family Medicine, University of VirginiaCharlottesvilleUnited States
| | - Iona Cheng
- Department of Epidemiology and Biostatistics, University of California, San FranciscoSan FranciscoUnited States
- University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San FranciscoSan FranciscoUnited States
| | - Rish K Pai
- Department of Pathology and Laboratory Medicine, Mayo ClinicScottsdaleUnited States
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterLos AngelesUnited States
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on CancerLyonFrance
| | - Marc J Gunter
- Nutrition and Metabolism Branch, International Agency for Research on CancerLyonFrance
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonLondonUnited Kingdom
| | - Nicholas J Timpson
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Emma E Vincent
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
- Translational Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
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15
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Bull CJ, Hazelwood E, Bell JA, Tan VY, Constantinescu AE, Borges MC, Legge DN, Burrows K, Huyghe JR, Brenner H, Castellví-Bel S, Chan AT, Kweon SS, Marchand LL, Li L, Cheng I, Pai RK, Figueiredo JC, Murphy N, Gunter MJ, Timpson NJ, Vincent EE. Identifying metabolic features of colorectal cancer liability using Mendelian randomization. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.03.10.23287084. [PMID: 36945480 PMCID: PMC10029059 DOI: 10.1101/2023.03.10.23287084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
Background Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. Methods To investigate whether changes in circulating metabolites characterise the early stages of colorectal cancer (CRC) development, we examined associations between a genetic risk score (GRS) associated with CRC liability (72 single nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N=6,221). Linear regression models were applied to examine associations between genetic liability to colorectal cancer and circulating metabolites measured in the same individuals at age 8, 16, 18 and 25 years. Results The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P<0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N=118,466, median age 58y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk. Conclusions These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism, and suggest that fatty acids may play an important role in CRC development. Funding This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.
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Affiliation(s)
- Caroline J. Bull
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Translational Health Sciences, Bristol Medical School, University of Bristol, UK
| | - Emma Hazelwood
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Joshua A. Bell
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Vanessa Y. Tan
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Andrei-Emil Constantinescu
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Maria Carolina Borges
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Danny N. Legge
- Translational Health Sciences, Bristol Medical School, University of Bristol, UK
| | - Kimberly Burrows
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Jeroen R. Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sergi Castellví-Bel
- Gastroenterology Department, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea
- Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | | | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Iona Cheng
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA
- University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, San Francisco, California, USA
| | - Rish K. Pai
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Arizona, Scottsdale, Arizona, USA
| | - Jane C. Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Marc J. Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom
| | - Nicholas J. Timpson
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Emma E. Vincent
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Translational Health Sciences, Bristol Medical School, University of Bristol, UK
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Beton-Mysur K, Brożek-Płuska B. A new modality for cholesterol impact tracking in colon cancer development - Raman imaging, fluorescence and AFM studies combined with chemometric analysis. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2023; 15:5199-5217. [PMID: 37781815 DOI: 10.1039/d3ay01040f] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. Obesity, alcohol consumption, smoking, high consumption of red or processed meat and a diet with low fibre, fruit, and vegetable intake increase CRC risk. Despite advances in surgery (the basic treatment for recovery), chemotherapy, and radiotherapy, CRC remains the second leading cause of cancer-related deaths in the world. Therefore the social importance of this problem stimulates research aimed at developing new tools for rapid CRC diagnosis and analysis of CRC risk factors. Considering the association between the cholesterol level and CRC, we hypothesize that cholesterol spectroscopic and AFM (atomic force microscopy) studies combined with chemometric analysis can be new, powerful tools used to visualize the cholesterol distribution, estimate cholesterol content and determine its influence on the biochemical and nanomechanical properties of colon cells. Our paper presents the analysis of human colon tissues: normal and cancer and human colon single cells normal CCD18-Co and cancer CaCo-2 in the physiological state and CaCo-2 upon mevastatin supplementation. Based on vibrational features we have shown that Raman spectroscopy and imaging allow cholesterol content in human colon tissues and human colon single cells of both types to be tracked and allow the effectiveness of mevastatin in the mevalonate pathway modulation and disruption of the cholesterol level to be proven. All observations have been confirmed by chemometric analysis including principal component analysis (PCA) and partial least squares discriminant analysis (PLSDA). The positive impact of statins on cholesterol content has also been studied by using fluorescence microscopy and atomic force microscopy (AFM). A significant increase in Young modulus as a mechanomarker for CaCo-2 human cancer colon cells upon mevastatin supplementation compared to CCD18-Co human normal colon cells was observed. This paper is one of the first reports about the use of Raman spectroscopic techniques in cholesterol investigations and the first one about cholesterol investigation using Raman spectroscopy (RS) on human cells ex vivo in the context of colon cancer development.
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Affiliation(s)
- K Beton-Mysur
- Lodz University of Technology, Faculty of Chemistry, Institute of Applied Radiation Chemistry, Laboratory of Laser Molecular Spectroscopy, Wroblewskiego 15, 93-590 Lodz, Poland.
| | - B Brożek-Płuska
- Lodz University of Technology, Faculty of Chemistry, Institute of Applied Radiation Chemistry, Laboratory of Laser Molecular Spectroscopy, Wroblewskiego 15, 93-590 Lodz, Poland.
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17
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Han N, Yuan M, Yan L, Tang H. Emerging Insights into Liver X Receptor α in the Tumorigenesis and Therapeutics of Human Cancers. Biomolecules 2023; 13:1184. [PMID: 37627249 PMCID: PMC10452869 DOI: 10.3390/biom13081184] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Liver X receptor α (LXRα), a member of the nuclear receptor superfamily, is identified as a protein activated by ligands that interacts with the promoters of specific genes. It regulates cholesterol, bile acid, and lipid metabolism in normal physiological processes, and it participates in the development of some related diseases. However, many studies have demonstrated that LXRα is also involved in regulating numerous human malignancies. Aberrant LXRα expression is emerging as a fundamental and pivotal factor in cancer cell proliferation, invasion, apoptosis, and metastasis. Herein, we outline the expression levels of LXRα between tumor tissues and normal tissues via the Oncomine and Tumor Immune Estimation Resource (TIMER) 2.0 databases; summarize emerging insights into the roles of LXRα in the development, progression, and treatment of different human cancers and their diversified mechanisms; and highlight that LXRα can be a biomarker and therapeutic target in diverse cancers.
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Affiliation(s)
- Ning Han
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Man Yuan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Libo Yan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
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18
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Tan M, Yang S, Xu X. High-density lipoprotein cholesterol and carcinogenesis. Trends Endocrinol Metab 2023; 34:303-313. [PMID: 36973155 DOI: 10.1016/j.tem.2023.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 02/27/2023] [Accepted: 02/27/2023] [Indexed: 03/29/2023]
Abstract
High-density lipoprotein cholesterol (HDLC) has been recognized to be associated with atherosclerosis. In the past few years many studies have found that HDLC is also related to tumor development and progression. Despite some opposing views, a large number of studies support a negative association between HDLC and tumor incidence. Measuring serum HDLC concentrations may facilitate assessment of the prognosis of cancer patients and provide a biomarker for tumors. However, there is a lack of molecular mechanism studies on the link between HDLC and tumors. In this review we discuss the impact of HDLC on the incidence and prognosis of cancer in different systems, as well as prospects for the prediction and treatment of cancer in the future.
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Affiliation(s)
- Meijuan Tan
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shijie Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiequn Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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19
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Yun Z, Nan M, Li X, Liu Z, Xu J, Du X, Dong Q, Hou L. Processed meat, red meat, white meat, and digestive tract cancers: A two-sample Mendelian randomization study. Front Nutr 2023; 10:1078963. [PMID: 36860687 PMCID: PMC9968810 DOI: 10.3389/fnut.2023.1078963] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/20/2023] [Indexed: 02/15/2023] Open
Abstract
Background Previous observational studies suggested inconsistent insights on the associations between meat intake and the risk of digestive tract cancers (DCTs). The causal effect of meat intake on DCTs is unclear. Methods Two-sample Mendelian randomization (MR) was performed based on genome-wide association studies (GWAS) summary data from UK Biobank and FinnGen to evaluate the causal effect of meat intake [processed meat, red meat (pork, beef, and lamb), and white meat (poultry)] on DCTs (esophageal, stomach, liver, biliary tract, pancreatic, and colorectal cancers). The causal effects were estimated using a primary analysis that employed inverse-variance weighting (IVW) and complementary analysis that utilized MR-Egger weighted by the median. A sensitivity analysis was conducted using the Cochran Q statistic, a funnel plot, the MR-Egger intercept, and a leave-one-out approach. MR-PRESSO and Radial MR were performed to identify and remove outliers. To demonstrate direct causal effects, multivariable MR (MVMR) was applied. In addition, risk factors were introduced to explore potential mediators of the relationship between exposure and outcome. Results The results of the univariable MR analysis indicated that genetically proxied processed meat intake was associated with an increased risk of colorectal cancer [IVW: odds ratio (OR) = 2.12, 95% confidence interval (CI) 1.07-4.19; P = 0.031]. The causal effect is consistent in MVMR (OR = 3.85, 95% CI 1.14-13.04; P = 0.030) after controlling for the influence of other types of exposure. The body mass index and total cholesterol did not mediate the causal effects described above. There was no evidence to support the causal effects of processed meat intake on other cancers, except for colorectal cancer. Similarly, there is no causal association between red meat, white meat intake, and DCTs. Conclusions Our study reported that processed meat intake increases the risk of colorectal cancer rather than other DCTs. No causal relationship was observed between red and white meat intake and DCTs.
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Affiliation(s)
| | | | | | - Zhu Liu
- Department of Hematology and Oncology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jing Xu
- Department of Hematology and Oncology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaofeng Du
- Department of Hematology and Oncology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | | | - Li Hou
- *Correspondence: Li Hou ✉
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20
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Iwagami M, Goto A, Katagiri R, Sutoh Y, Koyanagi YN, Nakatochi M, Nakano S, Hanyuda A, Narita A, Shimizu A, Tanno K, Hozawa A, Kinoshita K, Oze I, Ito H, Yamaji T, Sawada N, Nakamura Y, Nakamura S, Kuriki K, Suzuki S, Hishida A, Kasugai Y, Imoto I, Suzuki M, Momozawa Y, Takeuchi K, Yamamoto M, Sasaki M, Matsuo K, Tsugane S, Wakai K, Iwasaki M. Blood Lipids and the Risk of Colorectal Cancer: Mendelian Randomization Analyses in the Japanese Consortium of Genetic Epidemiology Studies. Cancer Prev Res (Phila) 2022; 15:827-836. [PMID: 36040498 DOI: 10.1158/1940-6207.capr-22-0146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 07/07/2022] [Accepted: 08/25/2022] [Indexed: 01/31/2023]
Abstract
The associations between blood lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides, and low-density lipoprotein cholesterol (LDL-C), and colorectal cancer risk are controversial. We evaluated potential causal relationships between blood lipids and colorectal cancer risk. Using the baseline data from the Japanese Consortium of Genetic Epidemiology studies, we estimated the single-nucleotide polymorphism (SNP)-exposure associations (n = 34,546 for TC, n = 50,290 for HDL-C, n = 51,307 for triglycerides, and n = 30,305 for LDL-C). We also estimated the SNP-outcome associations in another Japanese dataset (n = 7,936 colorectal cancer cases and n = 38,042 controls). We conducted Mendelian randomization (MR) analyses for the association between each blood lipid type and the risk of colorectal cancer using an inverse variance-weighted method. The total variances explained by the selected SNPs in TC (68 SNPs), HDL-C (50 SNPs), log-transformed triglycerides (26 SNPs), and LDL-C (35 SNPs) were 7.0%, 10.0%, 6.2%, and 5.7%, respectively. The odds ratios for colorectal cancer were 1.15 [95% confidence interval (CI), 1.01-1.32] per 1 standard deviation (SD; 33.3 mg/dL) increase in TC, 1.11 (95% CI, 0.98-1.26) per 1 SD (15.4 mg/dL) increase in HDL-C, 1.06 (95% CI, 0.90-1.26) per 1 SD (0.5 log-mg/dL) increase in log-transformed triglycerides, and 1.17 (95% CI, 0.91-1.50) per 1 SD (29.6 mg/dL) increase in LDL-C. Sensitivity analyses consistently suggested the positive association between TC and colorectal cancer, whereas results of each lipid component were inconsistent. In conclusion, this large MR study of a Japanese population showed a potentially causal association between high TC and colorectal cancer risk, although the association between each lipid component and colorectal cancer remained inconclusive. PREVENTION RELEVANCE In this large MR analysis of a Japanese population, a positive association was found between genetically predicted high total cholesterol (TC) levels and an increased risk of colorectal cancer. Therefore, lowering TC levels by lifestyle modifications or medications may be justified for the purpose of preventing colorectal cancer.
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Affiliation(s)
- Masao Iwagami
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.,Department of Health Services Research, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Atsushi Goto
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.,Department of Health Data Science, Graduate School of Data Science, Yokohama City University, Kanagawa, Japan
| | - Ryoko Katagiri
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Yoichi Sutoh
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank, Iwate, Japan
| | - Yuriko N Koyanagi
- Division of Cancer Information and Control, Aichi Cancer Center, Aichi, Japan
| | - Masahiro Nakatochi
- Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Shiori Nakano
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Akiko Hanyuda
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.,Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Akira Narita
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan
| | - Atsushi Shimizu
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank, Iwate, Japan
| | - Kozo Tanno
- Division of Clinical Research and Epidemiology, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan
| | - Atsushi Hozawa
- Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan
| | - Kengo Kinoshita
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan
| | - Isao Oze
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center, Aichi, Japan
| | - Hidemi Ito
- Division of Cancer Information and Control, Aichi Cancer Center, Aichi, Japan.,Division of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Taiki Yamaji
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Norie Sawada
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Yohko Nakamura
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Sho Nakamura
- Graduate School of Health Innovation, Kanagawa University of Human Services, Kanagawa, Japan.,Cancer Prevention and Control Division, Kanagawa Cancer Center Research Institute, Kanagawa, Japan
| | - Kiyonori Kuriki
- Laboratory of Public Health, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
| | - Sadao Suzuki
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan
| | - Asahi Hishida
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Yumiko Kasugai
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center, Aichi, Japan
| | - Issei Imoto
- Aichi Cancer Center Research Institute, Aichi, Japan
| | - Midori Suzuki
- Core Facilities, Aichi Cancer Center Research Institute, Aichi, Japan
| | - Yukihide Momozawa
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Kenji Takeuchi
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Masayuki Yamamoto
- Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan
| | - Makoto Sasaki
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center, Aichi, Japan.,Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Shoichiro Tsugane
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.,National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Motoki Iwasaki
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.,Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
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21
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Ejam SS, Saleh RO, Catalan Opulencia MJ, Najm MA, Makhmudova A, Jalil AT, Abdelbasset WK, Al-Gazally ME, Hammid AT, Mustafa YF, Sergeevna SE, Karampoor S, Mirzaei R. Pathogenic role of 25-hydroxycholesterol in cancer development and progression. Future Oncol 2022; 18:4415-4442. [PMID: 36651359 DOI: 10.2217/fon-2022-0819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 12/06/2022] [Indexed: 01/19/2023] Open
Abstract
Cholesterol is an essential lipid that serves several important functions, including maintaining the homeostasis of cells, acting as a precursor to bile acid and steroid hormones and preserving the stability of membrane lipid rafts. 25-hydroxycholesterol (25-HC) is a cholesterol derivative that may be formed from cholesterol. 25-HC is a crucial component in various biological activities, including cholesterol metabolism. In recent years, growing evidence has shown that 25-HC performs a critical function in the etiology of cancer, infectious diseases and autoimmune disorders. This review will summarize the latest findings regarding 25-HC, including its biogenesis, immunomodulatory properties and role in innate/adaptive immunity, inflammation and the development of various types of cancer.
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Affiliation(s)
| | - Raed Obaid Saleh
- Department of Pharmacy, Al-Maarif University College, Al-Anbar, Iraq
| | | | - Mazin Aa Najm
- Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Aziza Makhmudova
- Department of Social Sciences & Humanities, Samarkand State Medical Institute, Samarkand, Uzbekistan
- Department of Scientific Affairs, Tashkent State Dental Institute, Makhtumkuli Street 103, Tashkent, 100047, Uzbekistan
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | - Walid Kamal Abdelbasset
- Department of Health & Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | | | - Ali Thaeer Hammid
- Computer Engineering Techniques Department, Faculty of Information Technology, Imam Ja'afar Al-Sadiq University, Baghdad, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Sergushina Elena Sergeevna
- National Research Ogarev Mordovia State University, 68 Bolshevitskaya Street, Republic of Mordovia, Saransk, 430005, Russia
| | - Sajad Karampoor
- Gastrointestinal & Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Venom & Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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22
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Performance of the Use of Genetic Information to Assess the Risk of Colorectal Cancer in the Basque Population. Cancers (Basel) 2022; 14:cancers14174193. [PMID: 36077729 PMCID: PMC9454881 DOI: 10.3390/cancers14174193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/18/2022] [Accepted: 08/26/2022] [Indexed: 01/14/2023] Open
Abstract
Although the genetic contribution to colorectal cancer (CRC) has been studied in various populations, studies on the applicability of available genetic information in the Basque population are scarce. In total, 835 CRC cases and 940 controls from the Basque population were genotyped and genome-wide association studies were carried out. Mendelian Randomization analyses were used to discover the effect of modifiable risk factors and microbiota on CRC. In total, 25 polygenic risk score models were evaluated to assess their performance in CRC risk calculation. Moreover, 492 inflammatory bowel disease cases were used to assess whether that genetic information would not confuse both conditions. Five suggestive (p < 5 × 10−6) loci were associated with CRC risk, where genes previously associated with CRC were located (e.g., ABCA12, ATIC or ERBB4). Moreover, the analyses of CRC locations detected additional genes consistent with the biology of CRC. The possible contribution of cholesterol, BMI, Firmicutes and Cyanobacteria to CRC risk was detected by Mendelian Randomization. Finally, although polygenic risk score models showed variable performance, the best model performed correctly regardless of the location and did not misclassify inflammatory bowel disease cases. Our results are consistent with CRC biology and genetic risk models and could be applied to assess CRC risk in the Basque population.
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23
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Wu E, Ni J, Tao L, Xie T. A bidirectional Mendelian randomization study supports the causal effects of a high basal metabolic rate on colorectal cancer risk. PLoS One 2022; 17:e0273452. [PMID: 35994506 PMCID: PMC9394792 DOI: 10.1371/journal.pone.0273452] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 08/09/2022] [Indexed: 12/04/2022] Open
Abstract
Purpose We conducted a bidirectional two-sample Mendelian randomization (MR) study to determine whether genetically predicted basal metabolic rate (BMR) was a causal risk factor for colorectal cancer (CRC) or whether a genetically predicted CRC risk can influence the BMR level (i.e., reverse causation). Methods We employed 1,040 genetic variants as proxies for BMR to obtain effect estimates on CRC risk. Another 58 CRC-associated variants were used to estimate effects on BMR levels. Stratified analysis by tumor site was used to examine the causal associations between BMR and colon/rectal cancer risk. Results The inverse variance weighted (IVW) method indicated a significant causal effect of genetically determined BMR on CRC risk (ORSD = 1.27, 95% CI = 1.07–1.51). No significant reverse causal association was identified between genetically increased CRC risk and BMR levels [IVW (β = 0, 95% CI = -0.01 to 0)]. The results of MR-Egger and the weighted median method were consistent with the IVW method. Stratified analysis by CRC sites identified significant causal associations between BMR and colon cancer [IVW (ORSD = 1.45, 95% CI = 1.16-1-80)], and null evidence of a causal association between BMR and rectal cancer risk was found (p > 0.05). Conclusion Our findings add to the current literature by validating a positive relationship between high BMR levels and CRC risk instead of reverse causality. The genetically predicted BMR level was causally associated with colon cancer risk but not rectal cancer risk.
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Affiliation(s)
- E. Wu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Juntao Ni
- Women’s Hospital School of Medicine Zhejiang University, Hangzhou, Zhejiang, China
| | - Lin Tao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
- * E-mail: (LT); (TX)
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China
- * E-mail: (LT); (TX)
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24
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Deng Y, Wang L, Huang J, Ding H, Wong MCS. Associations between potential causal factors and colorectal cancer risk: A systematic review and meta-analysis of Mendelian randomization studies. J Dig Dis 2022; 23:435-445. [PMID: 36169182 DOI: 10.1111/1751-2980.13130] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/07/2022] [Accepted: 09/25/2022] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To summarize the associations between potential causal factors and colorectal cancer (CRC) risk based on existing Mendelian randomization studies. METHODS This systematic review and meta-analysis involved a literature search in Embase and Medline. All published articles using Mendelian randomization to explore potential causal factors of CRC were included. Studies that reported Mendelian randomization estimates of standard deviation changes in exposures were included in the meta-analysis. Subgroup analyses based on sex and anatomical sites were performed. RESULTS One hundred and ninety studies presented in 51 articles were included in systematic review, and 114 studies conducted in 32 articles were included in the meta-analysis. Adult body mass index, waist circumference, waist hip ratio, body height, body fat percentage, arm fat ratio, childhood obesity, lifetime cigarette consumption, short sleep, coffee consumption, and blood levels of vitamin B12 , arachidonic acid, stearic acid, and insulin-like growth factor binding protein 3 were positively associated with CRC risk. Conversely, acceleration-vector-magnitude physical activity, milk consumption, and blood levels of adiponectin, linoleic acid, α-linolenic acid, oleic acid, palmitoleic acid, interleukin-6 receptor subunit-α, and tumor necrosis factor were inversely associated with CRC risk. CONCLUSIONS Most obesity-related anthropometric characteristics, several unhealthy lifestyles, and blood levels of some micronutrients, fatty acids, and diabetes-related biomarkers were positively associated with CRC risk. In contrast, some lifestyles and blood levels of some fatty acids and inflammatory biomarkers were inversely associated with CRC risk. Future studies with more valid genetic variants are needed for factors with discrepancies between Mendelian randomization and epidemiological studies.
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Affiliation(s)
- Yunyang Deng
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lyu Wang
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Junjie Huang
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hanyue Ding
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Martin Chi Sang Wong
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China.,School of Public Health, the Chinese Academy of Medical Sciences and the Peking Union Medical College, Beijing, China.,School of Public Health, Peking University, Beijing, China
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25
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Hsu SH, Syu DK, Chen YC, Liu CK, Sun CA, Chen M. The Association between Hypertriglyceridemia and Colorectal Cancer: A Long-Term Community Cohort Study in Taiwan. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19137804. [PMID: 35805464 PMCID: PMC9265720 DOI: 10.3390/ijerph19137804] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 02/04/2023]
Abstract
(1) Background: Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer deaths worldwide. It often diagnosed at advanced stages, and with increasing incidence at younger generation. CRC poses a heavy financial burden and a huge public health challenge nowadays. Lipoproteins and serum lipids may have an influence on carcinogenesis by making oxidative stress, inflammation, and insulin resistance. Dyslipidemia plays a potential role in the risk of CRC. The purpose of this study is to use nationally representative samples to determine epidemiologic characteristics of CRC in the Taiwanese population, and to evaluate the associations between baseline levels of lipid profile and their effect on risk of colorectal cancer (CRC) comprehensively and quantitatively. The control of dyslipidemia in primary and secondary prevention may reduce the disease burden of CRC. (2) Methods: This is a nationwide long-term community-based prospective cohort study. Data were retrieved from the nationwide population-based Taiwanese Survey on Hypertension, Hyperglycemia and Hyperlipidemia (TwSHHH). Variables were estimated by the Cox proportional hazards model which was then further adjusted for age. We also calculated the relative ratios (RRs) of CRC for joint categories of serum cholesterol, triglyceride (TG), low-density lipoproteins cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) level, and to examine their combined effect and statistical interactions. (3) Results: Male, age, waist circumference, diabetes mellitus (DM), high TG, high cholesterol level, smoking history, and metabolic syndrome were proved to increase the risk of CRC. In addition, DM patients with a TG level ≥150 mg/dL and cholesterol ≥180 mg/dL had a 4.118-fold higher risk of CRC as compared with a TG level <150 mg/dL and cholesterol level <180 mg/dL, which was a significant difference (95% CI, 1.061−15.975; p = 0.0407). (4) Conclusions: Patients with DM should control TG and cholesterol level through diet, exercise, or taking medications more aggressively, not only for preventing cardiovascular disease, but also for first prevention of CRC. The study can be valuable for the clinicians and policy makers to implement more precisely goals about dyslipidemia management.
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Affiliation(s)
- Shu-Hua Hsu
- Department of Family Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University, No. 69, Guizi Rd., Taishan Dist., New Taipei City 24352, Taiwan;
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City 242062, Taiwan;
| | - De-Kai Syu
- Department of Orthopedics, Fu Jen Catholic University Hospital, Fu Jen Catholic University, No. 69, Guizi Rd., Taishan Dist., New Taipei City 24352, Taiwan;
| | - Yong-Chen Chen
- Master Program of Big Data in Biomedicine, College of Medicine, Fu Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City 242062, Taiwan;
- Data Science Center, College of Medicine, Fu Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City 242062, Taiwan
| | - Chih-Kuang Liu
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City 242062, Taiwan;
- Department of Urology, Fu Jen Catholic University Hospital, Fu Jen Catholic University, No. 69, Guizi Rd., Taishan Dist., New Taipei City 24352, Taiwan
| | - Chien-An Sun
- Data Science Center, College of Medicine, Fu Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City 242062, Taiwan
- Department of Public Health, College of Medicine, Fu Jen Catholic University, Xinzhuang Dist., New Taipei City 24205, Taiwan
- Correspondence: (C.-A.S.); (M.C.)
| | - Mingchih Chen
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City 242062, Taiwan;
- Artificial Intelligence Development Center, Fu Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City 242062, Taiwan
- Correspondence: (C.-A.S.); (M.C.)
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26
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Identification of ABCA5 among ATP-Binding Cassette Transporter Family as a New Biomarker for Colorectal Cancer. JOURNAL OF ONCOLOGY 2022; 2022:3399311. [PMID: 35783152 PMCID: PMC9242773 DOI: 10.1155/2022/3399311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 05/25/2022] [Indexed: 12/24/2022]
Abstract
Background The increasing incidence and mortality of colorectal cancer (CRC) urgently requires updated biomarkers. The ABC transporter family is a widespread family of membrane-bound proteins involved in the transportation of substrates associated with ATP hydrolysis, including metabolites, amino acids, peptides and proteins, sterols and lipids, organic and inorganic ions, sugars, metals, and drugs. They play an important role in the maintenance of homeostasis in the body. Purpose This study aims to search for new markers in the ABC transporter gene family for diagnostic and prognostic purposes through data mining of The Cancer Genome Atlas (TCGA) and GEO (Gene Expression Omnibus) datasets. Methods A total of 980 samples, including 684 CRC patients and 296 controls from five different datasets, were included for analysis. The construction of the PPI (protein-protein interaction) network and pathway analysis were performed in STRING database and DAVID (database for annotation, visualization, and integrated discovery), respectively. In addition, GSEA (gene set enrichment analysis) and WGCNA (weighted gene co-expression network analysis) were also used for functional analysis. Results After several rounds of screening and validation, only the ABCB5 gene was retained among the 49 genes. Conclusions The results demonstrated that ABCA5 expression is reduced in CRC and patients with high ABCA5 expression have better OS, which can provide guidance for better management and treatment of CRC in the future.
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27
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Nishiyama H, Funamizu T, Iwata H, Endo H, Chikata Y, Doi S, Wada H, Naito R, Ogita M, Kato Y, Okai I, Dohi T, Kasai T, Isoda K, Okazaki S, Miyauchi K, Minamino T. Low Apolipoprotein
A1
was associated with increased risk of cancer mortality in patients following percutaneous coronary intervention: A 10‐year follow‐up study. Int J Cancer 2022; 151:1482-1490. [PMID: 35796324 PMCID: PMC9540779 DOI: 10.1002/ijc.34164] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/12/2022] [Accepted: 05/24/2022] [Indexed: 11/11/2022]
Affiliation(s)
- Hiroki Nishiyama
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Takehiro Funamizu
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Hiroshi Iwata
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Hirohisa Endo
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Yuichi Chikata
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Shinichiro Doi
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Hideki Wada
- Department of Cardiology Juntendo University Shizuoka Hospital Shizuoka Japan
| | - Ryo Naito
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Manabu Ogita
- Department of Cardiology Juntendo University Shizuoka Hospital Shizuoka Japan
| | - Yoshiteru Kato
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Iwao Okai
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Tomotaka Dohi
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Takatoshi Kasai
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Kikuo Isoda
- Department of Cardiology Juntendo University Nerima Hospital Tokyo Japan
| | - Shinya Okazaki
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Katsumi Miyauchi
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
| | - Tohru Minamino
- Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine Tokyo Japan
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28
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MA Z, LI Z, WANG H, WANG R, HAN X. Screening of serum oxysterol biomarkers for colon cancer by liquid chromatography-tandem mass spectrometry. Se Pu 2022; 40:541-546. [PMID: 35616199 PMCID: PMC9404029 DOI: 10.3724/sp.j.1123.2022.01001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
结肠癌(CC)是全球常见恶性肿瘤之一,发病率呈逐年上升趋势,目前没有有效的标志物用于疾病早期诊断和干预跟踪。胆固醇及其氧化衍生物氧固醇在众多恶性肿瘤发生发展中发挥关键作用。该研究采用液相色谱-串联质谱(LC-MS/MS)技术,对CC临床血清样本中胆固醇及相关10种氧固醇代谢物进行了定性定量分析,并采用偏最小二乘判别分析(PLS-DA)和正交偏最小二乘判别分析(OPLS-DA)进行多元统计分析,发现上述目标代谢物能够较好地区分CC组与健康对照组。为防止数据过拟合,该研究在PLS-DA模型各代谢物变量投影重要性(VIP)基础上,结合最优组分数及K-均值聚类结果,筛选得到3种代谢标志物。通过受试者操作特征曲线(ROC)的曲线下面积(AUC)分析,发现筛选得到的3种潜在标志物联合预测CC达到0.998,说明模型性能优良。GO(基因本体论)富集分析显示3种潜在标志物主要分布在内质网和包被囊泡上,参与胆固醇代谢、运输、低密度脂蛋白重塑等生物进程,发挥胆固醇运输活性和低密度脂蛋白颗粒受体结合的分子功能。KEGG(京都基因与基因组百科全书)通路分析显示3种潜在标志物富集于类固醇生物合成、PPAR(过氧化物酶体增殖物激活受体)信号通路及ABC(ATP结合盒)转运等通路上。该研究为寻找CC标志物及进一步阐明胆固醇及氧固醇在CC发病过程中的作用奠定了一定的基础。
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29
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Sun Y, Liu B, Chen Y, Xing Y, Zhang Y. Multi-Omics Prognostic Signatures Based on Lipid Metabolism for Colorectal Cancer. Front Cell Dev Biol 2022; 9:811957. [PMID: 35223868 PMCID: PMC8874334 DOI: 10.3389/fcell.2021.811957] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022] Open
Abstract
Background: The potential biological processes and laws of the biological components in malignant tumors can be understood more systematically and comprehensively through multi-omics analysis. This study elaborately explored the role of lipid metabolism in the prognosis of colorectal cancer (CRC) from the metabonomics and transcriptomics. Methods: We performed K-means unsupervised clustering algorithm and t test to identify the differential lipid metabolites determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) in the serum of 236 CRC patients of the First Hospital of Jilin University (JLUFH). Cox regression analysis was used to identify prognosis-associated lipid metabolites and to construct multi-lipid-metabolite prognostic signature. The composite nomogram composed of independent prognostic factors was utilized to individually predict the outcome of CRC patients. Glycerophospholipid metabolism was the most significant enrichment pathway for lipid metabolites in CRC, whose related hub genes (GMRHGs) were distinguished by gene set variation analysis (GSVA) and weighted gene co-expression network analysis (WGCNA). Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis were utilized to develop the prognostic signature. Results: Six-lipid-metabolite and five-GMRHG prognostic signatures were developed, indicating favorable survival stratification effects on CRC patients. Using the independent prognostic factors as variables, we established a composite nomogram to individually evaluate the prognosis of CRC patients. The AUCs of one-, three-, and five-year ROC curves were 0.815, 0.815, and 0.805, respectively, showing auspicious prognostic accuracy. Furthermore, we explored the potential relationship between tumor microenvironment (TME) and immune infiltration. Moreover, the mutational frequency of TP53 in the high-risk group was significantly higher than that in the low-risk group (p < 0.001), while in the coordinate mutational status of TP53, the overall survival of CRC patients in the high-risk group was significantly lower than that in low-risk group with statistical differences. Conclusion: We identified the significance of lipid metabolism for the prognosis of CRC from the aspects of metabonomics and transcriptomics, which can provide a novel perspective for promoting individualized treatment and revealing the potential molecular biological characteristics of CRC. The composite nomogram including a six-lipid-metabolite prognostic signature is a promising predictor of the prognosis of CRC patients.
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30
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Markozannes G, Kanellopoulou A, Dimopoulou O, Kosmidis D, Zhang X, Wang L, Theodoratou E, Gill D, Burgess S, Tsilidis KK. Systematic review of Mendelian randomization studies on risk of cancer. BMC Med 2022; 20:41. [PMID: 35105367 PMCID: PMC8809022 DOI: 10.1186/s12916-022-02246-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 01/10/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence. METHODS We searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded. RESULTS We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer. CONCLUSIONS Despite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting.
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Affiliation(s)
- Georgios Markozannes
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
- Department of Epidemiology and Biostatistics, St. Mary's Campus, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK
| | - Afroditi Kanellopoulou
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | | | - Dimitrios Kosmidis
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Xiaomeng Zhang
- Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK
| | - Lijuan Wang
- Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK
| | - Evropi Theodoratou
- Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK
- CRUK Edinburgh Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, St. Mary's Campus, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK
| | - Stephen Burgess
- Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK
- Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Konstantinos K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
- Department of Epidemiology and Biostatistics, St. Mary's Campus, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK.
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Sassano M, Mariani M, Quaranta G, Pastorino R, Boccia S. Polygenic risk prediction models for colorectal cancer: a systematic review. BMC Cancer 2022; 22:65. [PMID: 35030997 PMCID: PMC8760647 DOI: 10.1186/s12885-021-09143-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 12/02/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Risk prediction models incorporating single nucleotide polymorphisms (SNPs) could lead to individualized prevention of colorectal cancer (CRC). However, the added value of incorporating SNPs into models with only traditional risk factors is still not clear. Hence, our primary aim was to summarize literature on risk prediction models including genetic variants for CRC, while our secondary aim was to evaluate the improvement of discriminatory accuracy when adding SNPs to a prediction model with only traditional risk factors. METHODS We conducted a systematic review on prediction models incorporating multiple SNPs for CRC risk prediction. We tested whether a significant trend in the increase of Area Under Curve (AUC) according to the number of SNPs could be observed, and estimated the correlation between AUC improvement and number of SNPs. We estimated pooled AUC improvement for SNP-enhanced models compared with non-SNP-enhanced models using random effects meta-analysis, and conducted meta-regression to investigate the association of specific factors with AUC improvement. RESULTS We included 33 studies, 78.79% using genetic risk scores to combine genetic data. We found no significant trend in AUC improvement according to the number of SNPs (p for trend = 0.774), and no correlation between the number of SNPs and AUC improvement (p = 0.695). Pooled AUC improvement was 0.040 (95% CI: 0.035, 0.045), and the number of cases in the study and the AUC of the starting model were inversely associated with AUC improvement obtained when adding SNPs to a prediction model. In addition, models constructed in Asian individuals achieved better AUC improvement with the incorporation of SNPs compared with those developed among individuals of European ancestry. CONCLUSIONS Though not conclusive, our results provide insights on factors influencing discriminatory accuracy of SNP-enhanced models. Genetic variants might be useful to inform stratified CRC screening in the future, but further research is needed.
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Affiliation(s)
- Michele Sassano
- Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168, Roma, Italy
| | - Marco Mariani
- Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168, Roma, Italy
| | - Gianluigi Quaranta
- Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168, Roma, Italy
- Department of Woman and Child Health and Public Health - Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Roberta Pastorino
- Department of Woman and Child Health and Public Health - Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
| | - Stefania Boccia
- Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168, Roma, Italy
- Department of Woman and Child Health and Public Health - Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
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Long-Term Statin Use, Total Cholesterol Level, and Risk of Colorectal Cancer: A Prospective Cohort Study. Am J Gastroenterol 2022; 117:158-166. [PMID: 34730560 PMCID: PMC9200604 DOI: 10.14309/ajg.0000000000001543] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 09/27/2021] [Indexed: 01/30/2023]
Abstract
INTRODUCTION Statin use has been examined as a potential chemopreventive strategy against colorectal cancer (CRC). Previous studies have not been able to investigate this topic with adequate follow-up time or disentangle the effects of statin use and total cholesterol level. We investigated prospectively this topic. METHODS Eligible participants (100,300 women and 47,991 men) in the Nurses' Health Study and Health Professionals Follow-Up Study were followed for up to 24 years. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. RESULTS We documented 2,924 incident CRC cases during follow-up. In fully adjusted analyses, longer duration of statin use was associated with higher risk of colon cancer (hazard ratios, the 95% confidence interval was 1.09, 0.95-1.25 for 1-5 years; 1.16, 0.99-1.36 for 6-10 years; 1.08, 0.81-1.44 for 11-15 years; 1.85, 1.30-2.61 for >15 years; vs never users, P = 0.004 for trend) rather than rectal cancer. The risk elevation was driven by proximal colon cancer (1.16, 0.98-1.38 for 1-5 years; 1.19, 0.98-1.45 for 6-10 years; 1.25, 0.89-1.74 for 11-15 years; 2.17, 1.46-3.24 for >15 years; vs never users, P = 0.001 for trend) rather than distal colon cancer. The results remained robust in analyses among participants with hypercholesterolemia or who never received screening. Total cholesterol level was not associated with CRC risk. DISCUSSION This study does not support benefit of statin use in CRC chemoprevention or any association between total cholesterol level and CRC risk. On the contrary, long-term statin use may be associated with increased colon cancer risk (driven by proximal colon cancer).
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Garcia-Etxebarria K, Clos-Garcia M, Telleria O, Nafría B, Alonso C, Iruarrizaga-Lejarreta M, Franke A, Crespo A, Iglesias A, Cubiella J, Bujanda L, Falcón-Pérez JM. Interplay between Genome, Metabolome and Microbiome in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13246216. [PMID: 34944836 PMCID: PMC8699218 DOI: 10.3390/cancers13246216] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/03/2021] [Accepted: 12/08/2021] [Indexed: 11/24/2022] Open
Abstract
Simple Summary The development of colorectal cancer (CRC) is influenced by the environment, genetics and microbiota. Microbiome and metabolome analyses allowed for the finding of factors and markers associated with adenoma and CRC risk, but the interaction of host genomics with those omic layers remains unclear. Thus, our aim is to add host genome information to find new factors and markers associated with adenoma and CRC risk or to propose biological mechanisms involved in the risk. We found interactions between different omic layers that could be biologically relevant, and the three layers gave complementary information to predict adenoma and CRC risk. Our findings will help to find new markers for adenoma and CRC risk and to analyze biological mechanisms involved in adenoma and CRC development. Abstract Background: Colorectal cancer (CRC), a major health concern, is developed depending on environmental, genetic and microbial factors. The microbiome and metabolome have been analyzed to study their role in CRC. However, the interplay of host genetics with those layers in CRC remains unclear. Methods: 120 individuals were sequenced and association analyses were carried out for adenoma and CRC risk, and for selected components of the microbiome and metabolome. The epistasis between genes located in cholesterol pathways was analyzed; modifiable risk factors were studied using Mendelian randomization; and the three omic layers were used to integrate their data and to build risk prediction models. Results: We detected genetic variants that were associated to components of metabolome or microbiome and adenoma or CRC risk (e.g., in LINC01605, PROKR2 and CCSER1 genes). In addition, we found interactions between genes of cholesterol metabolism, and HDL cholesterol levels affected adenoma (p = 0.0448) and CRC (p = 0.0148) risk. The combination of the three omic layers to build risk prediction models reached high AUC values (>0.91). Conclusions: The use of the three omic layers allowed for the finding of biological mechanisms related to the development of adenoma and CRC, and each layer provided complementary information to build risk prediction models.
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Affiliation(s)
- Koldo Garcia-Etxebarria
- Grupo de Genética Gastrointestinal, Biodonostia, 20014 San Sebastián, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain; (J.C.); (L.B.); (J.M.F.-P.)
- Correspondence:
| | - Marc Clos-Garcia
- Exosomes Laboratory, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), 48160 Derio, Spain; (M.C.-G.); (O.T.)
- Grupo de Enfermedades Gastrointestinales, Biodonostia, Universidad del País Vasco (UPV/EHU), 20014 San Sebastián, Spain;
| | - Oiana Telleria
- Exosomes Laboratory, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), 48160 Derio, Spain; (M.C.-G.); (O.T.)
| | - Beatriz Nafría
- Grupo de Enfermedades Gastrointestinales, Biodonostia, Universidad del País Vasco (UPV/EHU), 20014 San Sebastián, Spain;
| | - Cristina Alonso
- OWL Metabolomics, Bizkaia Technology Park, 48160 Derio, Spain; (C.A.); (M.I.-L.)
| | | | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany;
| | - Anais Crespo
- Department of Gastroenterology, Instituto de Investigación Sanitario Galicia Sur, Complexo Hospitalario Universitario de Ourense, 32005 Ourense, Spain; (A.C.); (A.I.)
| | - Agueda Iglesias
- Department of Gastroenterology, Instituto de Investigación Sanitario Galicia Sur, Complexo Hospitalario Universitario de Ourense, 32005 Ourense, Spain; (A.C.); (A.I.)
| | - Joaquín Cubiella
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain; (J.C.); (L.B.); (J.M.F.-P.)
- Department of Gastroenterology, Instituto de Investigación Sanitario Galicia Sur, Complexo Hospitalario Universitario de Ourense, 32005 Ourense, Spain; (A.C.); (A.I.)
| | - Luis Bujanda
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain; (J.C.); (L.B.); (J.M.F.-P.)
- Grupo de Enfermedades Gastrointestinales, Biodonostia, Universidad del País Vasco (UPV/EHU), 20014 San Sebastián, Spain;
| | - Juan Manuel Falcón-Pérez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain; (J.C.); (L.B.); (J.M.F.-P.)
- Exosomes Laboratory, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), 48160 Derio, Spain; (M.C.-G.); (O.T.)
- Basque Foundation for Sciences, Ikerbasque, 48013 Bilbao, Spain
- Metabolomics Platform, Centro de Investigación Cooperativa en Biociencias (CIC bioGUNE), 48160 Derio, Spain
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Dong L, Yang X, Wang Y, Jin Y, Zhou Q, Chen G, Han S. Key Markers Involved in the Anticolon Cancer Response of CD8+ T Cells through the Regulation of Cholesterol Metabolism. JOURNAL OF ONCOLOGY 2021; 2021:9398661. [PMID: 34858500 PMCID: PMC8632400 DOI: 10.1155/2021/9398661] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/14/2021] [Accepted: 11/06/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND T cell-mediated antitumor immune response is the basis of colorectal cancer (CRC) immunotherapy. Cholesterol plays an important role in T cell signal transduction and function. Apolipoprotein E (APOE) plays a major role in cholesterol metabolism. OBJECTIVE To screen and analyze key markers involved in the anticolon cancer response of CD8+ T cells through the regulation of cholesterol metabolism. METHODS Based on the median cutoff of the expression value of APOE according to the data downloaded from The Cancer Genome Atlas and Gene Expression Omnibus database, patients were grouped into low and high expression groups. Differences in clinical factors were assessed, and survival analysis was performed. Differentially expressed genes (DEGs) in the high and low expression groups were screened, followed by the analysis of differences in tumor-infiltrating immune cells and weighted gene coexpression network analysis results. The closely related genes to APOE were identified, followed by enrichment analysis, protein-protein interaction (PPI) network analysis, and differential expression analysis. Immunohistochemical staining (IHC) was used to detect the expression of CD8 in CRC tissues. RESULTS There were significant differences in prognosis and pathologic_N between the APOE low and high expression groups. A total of 2,349 DEGs between the high and low expression groups were selected. A total of 967 genes were obtained from the blue and brown modules. The probability of distribution of CD8+ T cells differed significantly between the two groups, and 320 closely related DEGs of APOE were screened. Genes including the HLA gene family, B2M, IRF4, and STAT5A had a higher degree in the PPI network. GEO datasets verified the prognosis and the related DEGs of APOE. IHC staining verified the relationship between the distribution of CD8+ T cells and APOE expression. CONCLUSION Genes including the HLA gene family, B2M, IRF4, and STAT5A might be the key genes involved in the anticolon cancer response of CD8+ T cells through the regulation of cholesterol metabolism.
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Affiliation(s)
- Liang Dong
- Department of Gastroenterology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Sanhuan North Road No. 1558, Wuxing District, Huzhou 313000, Zhejiang, China
| | - Xi Yang
- Department of Intervention and Radiotherapy, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, Zhejiang, China
| | - Yangyanqiu Wang
- Graduate School of Medical College of Zhejiang University, Kaixuan Road No. 268, Jianggan District, Hangzhou 310029, Zhejiang, China
| | - Yin Jin
- Department of Laboratory Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, Zhejiang, China
| | - Qing Zhou
- Department of Nursing, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Sanhuan North Road No.1558, Wuxing District, Huzhou 313000, Zhejiang, China
| | - Gong Chen
- Undergraduate School of Clinic Medicine, Huzhou University, Huzhou 313000, Zhejiang, China
| | - Shuwen Han
- Department of Oncology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, Zhejiang, China
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Yang C, Huang S, Cao F, Zheng Y. A lipid metabolism-related genes prognosis biomarker associated with the tumor immune microenvironment in colorectal carcinoma. BMC Cancer 2021; 21:1182. [PMID: 34740325 PMCID: PMC8571885 DOI: 10.1186/s12885-021-08902-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 10/18/2021] [Indexed: 02/08/2023] Open
Abstract
Background and aim Lipid metabolic reprogramming is considered to be a new hallmark of malignant tumors. The purpose of this study was to explore the expression profiles of lipid metabolism-related genes (LMRG) in colorectal cancer (CRC). Methods The lipid metabolism statuses of 500 CRC patients from the Cancer Genome Atlas (TCGA) and 523 from the Gene Expression Omnibus (GEO GSE39582) database were analyzed. The risk signature was constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression. Results A novel four-LMRG signature (PROCA1, CCKBR, CPT2, and FDFT1) was constructed to predict clinical outcomes in CRC patients. The risk signature was shown to be an independent prognostic factor for CRC and was associated with tumour malignancy. Principal components analysis demonstrated that the risk signature could distinguish between low- and high-risk patients. There were significantly differences in abundances of tumor-infiltrating immune cells and mutational landscape between the two risk groups. Patients in the low-risk group were more likely to have higher tumor mutational burden, stem cell characteristics, and higher PD-L1 expression levels. Furthermore, a genomic-clinicopathologic nomogram was established and shown to be a more effective risk stratification tool than any clinical parameter alone. Conclusions This study demonstrated the prognostic value of LMRG and showed that they may be partially involved in the suppressive immune microenvironment formation. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08902-5.
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Affiliation(s)
- Chao Yang
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, No. 99 ZhangZhiDong Street Wuchang District, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Shuoyang Huang
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, No. 99 ZhangZhiDong Street Wuchang District, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Fengyu Cao
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, No. 99 ZhangZhiDong Street Wuchang District, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Yongbin Zheng
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, No. 99 ZhangZhiDong Street Wuchang District, Wuhan, 430060, Hubei Province, People's Republic of China.
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Luo X, Tu Z, Chen H, Ding J. Blood lipids and risk of colon or rectal cancer: a Mendelian randomization study. J Cancer Res Clin Oncol 2021; 147:3591-3599. [PMID: 34490583 DOI: 10.1007/s00432-021-03790-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 08/31/2021] [Indexed: 11/24/2022]
Abstract
PURPOSE Recent Mendelian randomization (MR) studies derived inconsistent results of blood lipids' effect on colorectal cancer, and whether the blood lipids' effect on colon and rectal cancer is different is still unknown. Here, we sought to answer these questions. METHODS Primarily, we employed univariable MR to explore the blood lipids' effect on colon and rectal cancer, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol and triglycerides. Then, multivariable MR was also employed to reassess each blood lipid's effect on the two cancers with adjustment of the other lipids. Reverse MR analysis was adopted to determine whether colon or rectal cancer could affect the levels of blood lipids. The Cochrane's Q value was used to evaluate the heterogeneity, and MR-PRESSO was used to appraise the pleiotropy. RESULTS Generally, we did not find any significant result between blood lipids and the colon/rectal cancer after Bonferroni correction in the univariable MR analysis. The multivariable MR analysis also obtained the same results. However, it should be noted that higher total cholesterol level might increase the risk of colon cancer (OR = 1.15 [1.01, 1.31], IVW p value = 0.029) but not rectal cancer (OR = 1.02 [0.85, 1.21], IVW p value = 0.853). Such causal relationship turned insignificant in the multivariable MR. The reverse MR analysis suggested that either colon or rectal cancer could increase the levels of blood lipids. CONCLUSION We found no association between blood lipids and risk of colon or rectal cancer, except for a positive association between total cholesterol and colon cancer risk.
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Affiliation(s)
- Xuexin Luo
- Department of Chinese Traditional Medicine, The Second Hospital of Shaoxing, Shaoxing, Zhejiang, China
| | - Zhenxing Tu
- Department of Hand Surgery, The Second Hospital of Tangshan, Tangshan, Hebei Province, China
| | - Hongquan Chen
- Department of Bone Surgery, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Jie Ding
- Cancer Center, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, 68 Gehu Road, Wujin District, Changzhou, 213164, Jiangsu, China.
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Vaughan-Shaw PG, Timofeeva M, Ooi LY, Svinti V, Grimes G, Smillie C, Blackmur JP, Donnelly K, Theodoratou E, Campbell H, Zgaga L, Din FVN, Farrington SM, Dunlop MG. Differential genetic influences over colorectal cancer risk and gene expression in large bowel mucosa. Int J Cancer 2021; 149:1100-1108. [PMID: 33937989 DOI: 10.1002/ijc.33616] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 03/05/2021] [Accepted: 03/31/2021] [Indexed: 12/30/2022]
Abstract
Site-specific variation in colorectal cancer (CRC) incidence, biology and prognosis are poorly understood. We sought to determine whether common genetic variants influencing CRC risk might exhibit topographical differences on CRC risk through regional differences in effects on gene expression in the large bowel mucosa. We conducted a site-specific genetic association study (10 630 cases, 31 331 controls) to identify whether established risk variants exert differential effects on risk of proximal, compared to distal CRC. We collected normal colorectal mucosa and blood from 481 subjects and assessed mucosal gene expression using Illumina HumanHT-12v4 arrays in relation to germline genotype. Expression quantitative trait loci (eQTLs) were explored by anatomical location of sampling. The rs3087967 genotype (chr11q23.1 risk variant) exhibited significant site-specific effects-risk of distal CRC (odds ratio [OR] = 1.20, P = 8.20 × 10-20 ) with negligible effects on proximal CRC risk (OR = 1.05, P = .10). Expression of 1261 genes differed between proximal and distal colonic mucosa (top hit PRAC gene, fold-difference = 10, P = 3.48 × 10-57 ). In eQTL studies, rs3087967 genotype was associated with expression of 8 cis- and 21 trans-genes. Four of these (AKAP14, ADH5P4, ASGR2, RP11-342M1.7) showed differential effects by site, with strongest trans-eQTL signals in proximal colonic mucosa (eg, AKAP14, beta = 0.61, P = 5.02 × 10-5 ) and opposite signals in distal mucosa (AKAP14, beta = -0.17, P = .04). In summary, genetic variation at the chr11q23.1 risk locus imparts greater risk of distal rather than proximal CRC and exhibits site-specific differences in eQTL effects in normal mucosa. Topographical differences in genomic control over gene expression relevant to CRC risk may underlie site-specific variation in CRC. Results may inform individualised CRC screening programmes.
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Affiliation(s)
- Peter G Vaughan-Shaw
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Maria Timofeeva
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Department of Public Health, D-IAS, Danish Institute for Advanced Study, University of Southern Denmark, Odense, Denmark
| | - Li-Yin Ooi
- Department of Pathology, National University Hospital, Singapore
| | - Victoria Svinti
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Graeme Grimes
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Claire Smillie
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - James P Blackmur
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Kevin Donnelly
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Evi Theodoratou
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
| | - Harry Campbell
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
| | - Lina Zgaga
- Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland
| | - Farhat V N Din
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Susan M Farrington
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Malcolm G Dunlop
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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Tsilidis KK, Papadimitriou N, Dimou N, Gill D, Lewis SJ, Martin RM, Murphy N, Markozannes G, Zuber V, Cross AJ, Burrows K, Lopez DS, Key TJ, Travis RC, Perez-Cornago A, Hunter DJ, van Duijnhoven FJB, Albanes D, Arndt V, Berndt SI, Bézieau S, Bishop DT, Boehm J, Brenner H, Burnett-Hartman A, Campbell PT, Casey G, Castellví-Bel S, Chan AT, Chang-Claude J, de la Chapelle A, Figueiredo JC, Gallinger SJ, Giles GG, Goodman PJ, Gsur A, Hampe J, Hampel H, Hoffmeister M, Jenkins MA, Keku TO, Kweon SS, Larsson SC, Le Marchand L, Li CI, Li L, Lindblom A, Martín V, Milne RL, Moreno V, Nan H, Nassir R, Newcomb PA, Offit K, Pharoah PDP, Platz EA, Potter JD, Qi L, Rennert G, Sakoda LC, Schafmayer C, Slattery ML, Snetselaar L, Schenk J, Thibodeau SN, Ulrich CM, Van Guelpen B, Harlid S, Visvanathan K, Vodickova L, Wang H, White E, Wolk A, Woods MO, Wu AH, Zheng W, Bueno-de-Mesquita B, Boutron-Ruault MC, Hughes DJ, Jakszyn P, Kühn T, Palli D, Riboli E, Giovannucci EL, Banbury BL, Gruber SB, Peters U, Gunter MJ. Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study. Am J Clin Nutr 2021; 113:1490-1502. [PMID: 33740060 PMCID: PMC8168352 DOI: 10.1093/ajcn/nqab003] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 01/04/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. OBJECTIVES To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. RESULTS Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk. CONCLUSIONS These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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Affiliation(s)
- Konstantinos K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Nikos Papadimitriou
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Niki Dimou
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Sarah J Lewis
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Richard M Martin
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- University Hospitals Bristol National Health Service Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, United Kingdom
| | - Neil Murphy
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Georgios Markozannes
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Verena Zuber
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- Medical Research Council Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Kimberley Burrows
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - David S Lopez
- Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX, USA
| | - Timothy J Key
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Ruth C Travis
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Aurora Perez-Cornago
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - David J Hunter
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | | | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Stéphane Bézieau
- Medical Genetics Service, University Hospital Center (CHU) Nantes, Nantes, France
| | - D Timothy Bishop
- , Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Juergen Boehm
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Peter T Campbell
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Sergi Castellví-Bel
- Gastroenterology Department, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Biomedical Research Network Center for Liver and Digestive Diseases (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA
- Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg, Hamburg, Germany
| | - Albert de la Chapelle
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Steven J Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Graham G Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Phyllis J Goodman
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Andrea Gsur
- Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria
| | - Jochen Hampe
- Department of Medicine I, University Hospital Dresden, Dresden University of Technology (TU Dresden), Dresden, Germany
| | - Heather Hampel
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Temitope O Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
- Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea
| | - Susanna C Larsson
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | | | - Christopher I Li
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
| | - Annika Lindblom
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Vicente Martín
- CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Biomedicine Institute (IBIOMED), University of León, León, Spain
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Victor Moreno
- CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Oncology Data Analytics Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
- ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Hongmei Nan
- Department of Epidemiology, Richard M Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA
- IU Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA
| | - Rami Nassir
- Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | - Kenneth Offit
- Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Paul D P Pharoah
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Centre for Public Health Research, Massey University, Wellington, New Zealand
| | - Lihong Qi
- Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA, USA
| | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Clemens Schafmayer
- Department of General Surgery, University Hospital Rostock, Rostock, Germany
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Linda Snetselaar
- Department of Epidemiology, University of Iowa College of Public Health, Iowa City, IA, USA
| | - Jeanette Schenk
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Stephen N Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Cornelia M Ulrich
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Hansong Wang
- University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Michael O Woods
- Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Anna H Wu
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Bas Bueno-de-Mesquita
- Formerly, Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Marie-Christine Boutron-Ruault
- Faculty of Medicine, CESP, University of Paris-Sud, Faculty of Medicine UVSQ, INSERM, University of Paris-Saclay, Villejuif, France
- Centre for Research in Epidemiology and Population Health (CESP), Gustave Roussy, Villejuif, France
| | - David J Hughes
- Cancer Biology and Therapeutics Group, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Paula Jakszyn
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Blanquerna Faculty of Health Sciences, Ramon Llull University, Barcelona, Spain
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Domenico Palli
- Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network-ISPRO, Florence, Italy
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Edward L Giovannucci
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA
- Department of Nutrition, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Barbara L Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Stephen B Gruber
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Marc J Gunter
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
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Zhao TJ, Zhu N, Shi YN, Wang YX, Zhang CJ, Deng CF, Liao DF, Qin L. Targeting HDL in tumor microenvironment: New hope for cancer therapy. J Cell Physiol 2021; 236:7853-7873. [PMID: 34018609 DOI: 10.1002/jcp.30412] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/16/2021] [Accepted: 04/24/2021] [Indexed: 12/12/2022]
Abstract
Epidemiological studies have shown that plasma HDL-C levels are closely related to the risk of prostate cancer, breast cancer, and other malignancies. As one of the key carriers of cholesterol regulation, high-density lipoprotein (HDL) plays an important role in tumorigenesis and cancer development through anti-inflammation, antioxidation, immune-modulation, and mediating cholesterol transportation in cancer cells and noncancer cells. In addition, the occurrence and progression of cancer are closely related to the alteration of the tumor microenvironment (TME). Cancer cells synthesize and secrete a variety of cytokines and other factors to promote the reprogramming of surrounding cells and shape the microenvironment suitable for cancer survival. By analyzing the effect of HDL on the infiltrating immune cells in the TME, as well as the relationship between HDL and tumor-associated angiogenesis, it is suggested that a moderate increase in the level of HDL in vivo with consequent improvement of the function of HDL in the TME and induction of intracellular cholesterol efflux may be a promising strategy for cancer therapy.
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Affiliation(s)
- Tan-Jun Zhao
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Neng Zhu
- Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Ya-Ning Shi
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Yu-Xiang Wang
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Chan-Juan Zhang
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Chang-Feng Deng
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Duan-Fang Liao
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Li Qin
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
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Passarelli MN, Thompson BM, McDonald JG, Snover DC, Palys TJ, Rees JR, Barry EL, Baron JA. Circulating 27-hydroxycholesterol and Risk of Colorectal Adenomas and Serrated Polyps. Cancer Prev Res (Phila) 2021; 14:479-488. [PMID: 33408073 PMCID: PMC8026496 DOI: 10.1158/1940-6207.capr-20-0414] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/16/2020] [Accepted: 12/23/2020] [Indexed: 11/16/2022]
Abstract
The oxysterol 27-hydroxycholesterol (27-OHC) is an endogenous selective estrogen receptor modulator implicated in breast cancer etiology. It is unknown whether circulating 27-OHC is associated with colorectal neoplasia risk. Circulating 27-OHC was measured using LC/MS in fasting plasma collected at baseline from participants of the Vitamin D/Calcium Polyp Prevention Study, a completed randomized clinical trial. Participants were between 45 and 75 years old, recently diagnosed with ≥1 colorectal adenoma, and followed for new colorectal polyps during colonoscopic surveillance. Adjusted risk ratios (RR) with 95% confidence intervals (CI) of new colorectal polyps were estimated for quartiles of circulating 27-OHC using log-linear regression for repeated outcomes. Polyp phenotypes included any adenomas, advanced adenomas, hyperplastic polyps, and sessile serrated adenomas/polyps. Circulating 27-OHC was measured at baseline for 1,246 participants. Compared with participants with circulating 27-OHC below the first quartile (<138 ng/mL), those with circulating 27-OHC at or above the fourth quartile (≥201 ng/mL) had 24% higher risk of adenomas (RR, 1.24; 95% CI, 1.05-1.47) and 89% higher risk of advanced adenomas (RR, 1.89; 95% CI, 1.17-3.06). Stronger associations were observed among participants with advanced adenomas at baseline. Circulating 27-OHC was not associated with risk of hyperplastic polyps (RR, 0.90; 95% CI, 0.66-1.22) or sessile serrated adenomas/polyps (RR, 1.02; 95% CI, 0.50-2.07). Circulating 27-OHC may be a risk factor for colorectal adenomas but not serrated polyps. PREVENTION RELEVANCE: This study found that plasma concentration of 27-hydroxycholesterol, a metabolite of cholesterol that regulates lipid metabolism and acts as a selective estrogen receptor modulator, is associated with the risk of developing precursor lesions for colorectal cancer.
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Affiliation(s)
- Michael N Passarelli
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
| | - Bonne M Thompson
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jeffrey G McDonald
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Dale C Snover
- Department of Pathology, Fairview Southdale Hospital, Edina, Minnesota
| | - Thomas J Palys
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Judy R Rees
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Elizabeth L Barry
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - John A Baron
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina
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Revealing the Role of High-Density Lipoprotein in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22073352. [PMID: 33805921 PMCID: PMC8037642 DOI: 10.3390/ijms22073352] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/11/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a highly prevalent malignancy with multifactorial etiology, which includes metabolic alterations as contributors to disease development. Studies have shown that lipid status disorders are involved in colorectal carcinogenesis. In line with this, previous studies have also suggested that the serum high-density lipoprotein cholesterol (HDL-C) level decreases in patients with CRC, but more recently, the focus of investigations has shifted toward the exploration of qualitative properties of HDL in this malignancy. Herein, a comprehensive overview of available evidences regarding the putative role of HDL in CRC will be presented. We will analyze existing findings regarding alterations of HDL-C levels but also HDL particle structure and distribution in CRC. In addition, changes in HDL functionality in this malignancy will be discussed. Moreover, we will focus on the genetic regulation of HDL metabolism, as well as the involvement of HDL in disturbances of cholesterol trafficking in CRC. Finally, possible therapeutic implications related to HDL will be presented. Given the available evidence, future studies are needed to resolve all raised issues concerning the suggested protective role of HDL in CRC, its presumed function as a biomarker, and eventual therapeutic approaches based on HDL.
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Mayengbam SS, Singh A, Pillai AD, Bhat MK. Influence of cholesterol on cancer progression and therapy. Transl Oncol 2021; 14:101043. [PMID: 33751965 PMCID: PMC8010885 DOI: 10.1016/j.tranon.2021.101043] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/24/2021] [Accepted: 02/11/2021] [Indexed: 12/24/2022] Open
Abstract
Abnormality in blood cholesterol level is significantly correlated with risk of different cancers. Majority of tumor tissue from cancer patient exhibits overexpression of LDLR and ACAT for supporting rapid cancer cell proliferation. Alteration of the cholesterol metabolism in cancer cells hampers therapeutic response. Targeting cholesterol metabolism for treatment of cancer with other conventional chemotherapeutic drugs appears to be beneficial. Cholesterol is a fundamental molecule necessary for the maintenance of cell structure and is vital to various normal biological functions. It is a key factor in lifestyle-related diseases including obesity, diabetes, cardiovascular disease, and cancer. Owing to its altered serum chemistry status under pathological states, it is now being investigated to unravel the mechanism by which it triggers various health complications. Numerous clinical studies in cancer patients indicate an alteration in blood cholesterol level (either decreased or increased) in comparison to normal healthy individuals. This article elaborates on our understanding as to how cholesterol is being hijacked in the malignancy for the development, survival, stemness, progression, and metastasis of cancerous cells. Also, it provides a glimpse of how cholesterol derived entities, alters the signaling pathway towards their advantage. Moreover, deregulation of the cholesterol metabolism pathway has been often reported to hamper various treatment strategies in different cancer. In this context, attempts have been made to bring forth its relevance in being targeted, in pre-clinical and clinical studies for various treatment modalities. Thus, understanding the role of cholesterol and deciphering associated molecular mechanisms in cancer progression and therapy are of relevance towards improvement in the management of various cancers.
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Affiliation(s)
| | - Abhijeet Singh
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411 007, India
| | - Ajay D Pillai
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411 007, India
| | - Manoj Kumar Bhat
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411 007, India.
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Xu L, Cai J, Gao T, Ma A. Shellfish consumption and health: A comprehensive review of human studies and recommendations for enhanced public policy. Crit Rev Food Sci Nutr 2021; 62:4656-4668. [PMID: 33527847 DOI: 10.1080/10408398.2021.1878098] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Shellfish, including various species of mollusks (e.g., clams, oysters, and mussels) and crustaceans (e.g., shrimp and crab), have been a cornerstone of healthy dietary recommendations. However, beyond providing basic nutrition needs, their health-promoting effects have been suggested to include inflammation reduction and prevention of various chronic non-communicable diseases. Currently, studies on the association between shellfish consumption and health outcomes have reported conflicting results. The present comprehensive review summarized the latest studies on shellfish consumption and synthesized the available evidence on the potential health benefits or risks of shellfish consumption. The findings demonstrated that shellfish consumption may increase the risk of hyperuricemia and gout but may not increase the risk of type 2 diabetes, cardiovascular diseases, and thyroid cancer. Adequate evidence is lacking on the association between shellfish consumption and the risk of colorectal cancer, pancreatic cancer, oral cancer, endometriosis, hip fracture, cognitive function, wheeze, eczema and food allergy. Raw shellfish consumption may cause gastroenteritis and other diseases infected by bacteria or viruses. This review thus provides consumers and other relevant stakeholders with the latest evidence-based information on the potential benefits and risks of shellfish consumption.
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Affiliation(s)
- Lei Xu
- Institute of Nutrition and Health, School of Public Health, Qingdao University, Qngdao, China
| | - Jing Cai
- Institute of Nutrition and Health, School of Public Health, Qingdao University, Qngdao, China
| | - Tianlin Gao
- Institute of Nutrition and Health, School of Public Health, Qingdao University, Qngdao, China
| | - Aiguo Ma
- Institute of Nutrition and Health, School of Public Health, Qingdao University, Qngdao, China
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Lipid Level, Lipid Variability, and Risk of Multiple Myeloma: A Nationwide Population-Based Study of 3,527,776 Subjects. Cancers (Basel) 2021; 13:cancers13030540. [PMID: 33572660 PMCID: PMC7866996 DOI: 10.3390/cancers13030540] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary There is preclinical evidence that abnormalities in lipid metabolism promote cancer development, and a few studies show the association between lipid levels and multiple myeloma (MM). However, to our knowledge, the role of lipid variability as a risk factor for MM has not been evaluated. We investigated whether lipid level and its variability are associated with the development of MM at a population level. Lower baseline lipid levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides, and high variability in high-density lipoprotein cholesterol were all associated with increased risk of developing MM. These findings support the role of lipid metabolism in MM risk. Abstract (1) Background: There is evidence that abnormality in lipid metabolism promotes cancer development. This study investigated whether lipid level and its variability are associated with the development of MM at a population level. (2) Methods: A retrospective cohort study included a total of 3,527,776 subjects aged 40 and above who participated in ≥3 health examinations within the previous five years, including the index year (2012–2013). Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) were measured, and visit-to-visit lipid variability were calculated by variability independent of the mean (VIM) method. The study population was followed from the health examination date in the index year until the diagnosis of MM, death, or the last follow-up date (31 December 2017). (3) Results: During a median (5–95%) 5.1 years of follow-up, 969 subjects developed MM. A lower risk of MM was observed with higher quartiles of baseline lipid levels compared to the lowest quartile group (Q4 vs. Q1: adjusted hazard ratios (aHRs) 0.51, 95% confidence interval (CI) (0.42–0.61) for TC; 0.50 (0.41–0.61) for HDL-C; 0.65 (0.54–0.77) for LDL-C; and 0.72 (0.60–0.87) for TG in model (3). Among all lipid measures, only variability in HDL-C was associated with risk of MM: aHRs (95% CI) were 1.12 (0.91–1.38), 1.19 (0.97–1.46), and 1.34 (1.09–1.65) in the Q2, Q3, and Q4, respectively, compared to the Q1 of VIM of HDL-C. (4) Conclusions: This study shows that patients with lower lipid levels and high HDL-C variability are at increased risk of developing MM.
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Caramujo-Balseiro S, Faro C, Carvalho L. Metabolic pathways in sporadic colorectal carcinogenesis: A new proposal. Med Hypotheses 2021; 148:110512. [PMID: 33548761 DOI: 10.1016/j.mehy.2021.110512] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 01/09/2021] [Accepted: 01/22/2021] [Indexed: 02/07/2023]
Abstract
Given the reports made about geographical differences in Colorectal Cancer (CRC) occurrence, suggesting a link between dietary habits, genes and cancer risk, we hypothesise that there are four fundamental metabolic pathways involved in diet-genes interactions, directly implicated in colorectal carcinogenesis: folate metabolism; lipid metabolism; oxidative stress response; and inflammatory response. Supporting this hypothesis are the evidence given by the significant associations between several diet-genes polymorphisms and CRC, namely: MTHFR, MTR, MTRR and TS (involved in folate metabolism); NPY, APOA1, APOB, APOC3, APOE, CETP, LPL and PON1 (involved in lipid metabolism); MNSOD, SOD3, CAT, GSTP1, GSTT1 and GSTM1 (involved in oxidative stress response); and IL-1, IL-6, TNF-α, and TGF-β (involved in inflammatory response). We also highlight the association between some foods/nutrients/nutraceuticals that are important in CRC prevention or treatment and the four metabolic pathways proposed, and the recent results of genome-wide association studies, both assisting our hypothesis. Finally, we propose a new line of investigation with larger studies, using accurate dietary biomarkers and investigating the four metabolic pathways genes simultaneously. This line of investigation will be essential to understand the full complexity of the association between nature and nurture in CRC and perhaps in other types of cancers. Only with this in-depth knowledge will it be possible to make personalised nutrition recommendations for disease prevention and management.
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Affiliation(s)
- Sandra Caramujo-Balseiro
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine - University of Coimbra, Coimbra, Portugal; Department of Life Sciences - University of Coimbra, Coimbra, Portugal.
| | - Carlos Faro
- Department of Life Sciences - University of Coimbra, Coimbra, Portugal; UC Biotech, Cantanhede, Portugal
| | - Lina Carvalho
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine - University of Coimbra, Coimbra, Portugal
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Bull CJ, Bell JA, Murphy N, Sanderson E, Davey Smith G, Timpson NJ, Banbury BL, Albanes D, Berndt SI, Bézieau S, Bishop DT, Brenner H, Buchanan DD, Burnett-Hartman A, Casey G, Castellví-Bel S, Chan AT, Chang-Claude J, Cross AJ, de la Chapelle A, Figueiredo JC, Gallinger SJ, Gapstur SM, Giles GG, Gruber SB, Gsur A, Hampe J, Hampel H, Harrison TA, Hoffmeister M, Hsu L, Huang WY, Huyghe JR, Jenkins MA, Joshu CE, Keku TO, Kühn T, Kweon SS, Le Marchand L, Li CI, Li L, Lindblom A, Martín V, May AM, Milne RL, Moreno V, Newcomb PA, Offit K, Ogino S, Phipps AI, Platz EA, Potter JD, Qu C, Quirós JR, Rennert G, Riboli E, Sakoda LC, Schafmayer C, Schoen RE, Slattery ML, Tangen CM, Tsilidis KK, Ulrich CM, van Duijnhoven FJB, van Guelpen B, Visvanathan K, Vodicka P, Vodickova L, Wang H, White E, Wolk A, Woods MO, Wu AH, Campbell PT, Zheng W, Peters U, Vincent EE, Gunter MJ. Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study. BMC Med 2020; 18:396. [PMID: 33327948 PMCID: PMC7745469 DOI: 10.1186/s12916-020-01855-9] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 11/12/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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Affiliation(s)
- Caroline J Bull
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK.
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
| | - Joshua A Bell
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Neil Murphy
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Eleanor Sanderson
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - George Davey Smith
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Nicholas J Timpson
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Barbara L Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Stéphane Bézieau
- Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - D Timothy Bishop
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
- Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, Victoria, Australia
- Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | | | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Sergi Castellví-Bel
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Cancer Centre Hamburg (UCCH), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, UK
| | - Albert de la Chapelle
- Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Steven J Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Susan M Gapstur
- Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
| | - Graham G Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Stephen B Gruber
- Department of Preventive Medicine & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Andrea Gsur
- Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria
| | - Jochen Hampe
- Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Heather Hampel
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Wen-Yi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Corinne E Joshu
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Temitope O Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea
- Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea
| | | | - Christopher I Li
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
| | - Annika Lindblom
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Vicente Martín
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Biomedicine Institute (IBIOMED), University of León, León, Spain
| | - Anne M May
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Victor Moreno
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
- ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | - Kenneth Offit
- Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- University of Washington, Seattle, WA, USA
- Centre for Public Health Research, Massey University, Wellington, New Zealand
- Health Sciences Centre, University of Canterbury, Christchurch, New Zealand
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | | | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Clemens Schafmayer
- Department of General Surgery, University Hospital Rostock, Rostock, Germany
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Catherine M Tangen
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Kostas K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Cornelia M Ulrich
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | | | - Bethany van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Hansong Wang
- University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Michael O Woods
- Discipline of Genetics, Memorial University of Newfoundland, St John's, Canada
| | - Anna H Wu
- University of Southern California, Preventative Medicine, CA, Los Angeles, USA
| | - Peter T Campbell
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Emma E Vincent
- MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Marc J Gunter
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
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Madsen CM, Varbo A, Nordestgaard BG. Novel Insights From Human Studies on the Role of High-Density Lipoprotein in Mortality and Noncardiovascular Disease. Arterioscler Thromb Vasc Biol 2020; 41:128-140. [PMID: 33232200 DOI: 10.1161/atvbaha.120.314050] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The vast majority of research about HDL (high-density lipoprotein) has for decades revolved around the possible role of HDL in atherosclerosis and its therapeutic potential within cardiovascular disease prevention; however, failures with therapies aimed at increasing HDL cholesterol has left questions as to what the role and function of HDL in human health and disease is. Recent observational studies have further shown that extreme high HDL cholesterol is associated with high mortality leading to speculations that HDL could in some instances be harmful. In addition, evidence from observational, and to a lesser extent genetic studies has emerged indicating that HDL might be associated with the development of other major noncardiovascular diseases, such as infectious disease, autoimmune disease, cancer, type 2 diabetes, kidney disease, and lung disease. In this review, we discuss (1) the association between extreme high HDL cholesterol and mortality and (2) the emerging human evidence linking HDL to several major diseases outside the realm of cardiovascular disease.
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Affiliation(s)
- Christian M Madsen
- Department of Clinical Biochemistry (C.M.M., A.V., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.,The Copenhagen General Population Study (C.M.M., A.V., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (C.M.M., A.V., B.G.N.)
| | - Anette Varbo
- Department of Clinical Biochemistry (C.M.M., A.V., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.,The Copenhagen General Population Study (C.M.M., A.V., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (C.M.M., A.V., B.G.N.)
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry (C.M.M., A.V., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.,The Copenhagen General Population Study (C.M.M., A.V., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (C.M.M., A.V., B.G.N.).,The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Denmark (B.G.N.)
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Piccinin E, Cariello M, Moschetta A. Lipid metabolism in colon cancer: Role of Liver X Receptor (LXR) and Stearoyl-CoA Desaturase 1 (SCD1). Mol Aspects Med 2020; 78:100933. [PMID: 33218679 DOI: 10.1016/j.mam.2020.100933] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/01/2020] [Accepted: 11/09/2020] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the most commonly occurring cancers worldwide. Although several genetic alterations have been associated with CRC onset and progression, nowadays the reprogramming of cellular metabolism has been recognized as a fundamental step of the carcinogenic process. Intestinal tumor cells frequently display an aberrant activation of lipid metabolism. Indeed, to satisfy the growing needs of a continuous proliferation, cancer cells can either increase the uptake of exogenous lipids or upregulate the endogenous lipogenesis and cholesterol synthesis. Therefore, strategies aimed at limiting lipid accumulation are now under development in order to counteract malignancies. Two major players of lipids metabolism have been so far identified for their contribution to CRC development: the nuclear receptor Liver X Receptor (LXRs) and the enzyme Stearoyl-CoA Desaturase 1 (SCD1). Whereas LXR is mainly recognized for its role as a cholesterol sensor, finally promoting the loss of cellular cholesterol and whole-body homeostasis, SCD1 acts as the major regulator of new fatty acids, finely tuning the monounsaturated fatty acids (MUFA) to saturated fatty acids (SFA) ratio. Intriguingly, SCD1 is directly regulated by LXRs. Despite LXRs agonists have elicited great interest as a promising therapeutic target for cancer, LXR's ability to induce SCD1 and new fatty acids synthesis represent a major obstacle in the development of new effective treatments. Thus, further investigations are required to fully dissect the concomitant modulation of both players, to develop specific therapies aimed at blocking intestinal cancer cells proliferation, eventually counteracting CRC progression.
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Affiliation(s)
- Elena Piccinin
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy; Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari, Italy
| | - Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy; INBB, National Institute for Biostructures and Biosystems, Rome, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy; INBB, National Institute for Biostructures and Biosystems, Rome, Italy; National Cancer Center, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy.
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Zhou X, Lin N, Zhang M, Wang X, An Y, Su Q, Du P, Li B, Chen H. Circulating soluble receptor for advanced glycation end products and other factors in type 2 diabetes patients with colorectal cancer. BMC Endocr Disord 2020; 20:170. [PMID: 33187505 PMCID: PMC7666469 DOI: 10.1186/s12902-020-00647-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 10/31/2020] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Recent study showed that individuals with type 2 diabetes have a high risk of developing colorectal cancer (CRC), in which Receptor for Advanced Glycation End Products (RAGE) plays a pivotal role. We conducted a cross-sectional study to examine the relationships of circulating sRAGE, CRC and other clinical factors in type2 diabetes patients. METHODS A total of 150 type 2 diabetes patients aged 50 years and older were enrolled, including 50 patients with CRC and 100 patients without CRC. We measured Serum levels of sRAGE and interleukin-6(IL-6) using an enzyme-linked immunosorbent assay (ELISA). In addition, other clinical parameters were also measured during hospitalization. RESULTS Type 2 diabetes patients with CRC had higher triglyceride, total cholesterol, IL-6, and circulating sRAGE levels and lower use of medicines than type 2 diabetes patients without CRC. Circulating sRAGE was associated with an increased risk for CRC (OR = 2.289 for each SD increase in sRAGE, 95% CI = 1.037-5.051; P = 0.04) among Type 2 diabetes patients after adjustment for confounders. Furthermore, circulating sRAGE levels among type 2 diabetes patients were positively correlated with triglyceride (r = 0.377, P < 0.001), total cholesterol (r = 0.491, P < 0.001), and low-density lipoprotein cholesterol (LDL-c)(r = 0.330, P < 0.001) levels; the homeostatic model assessment for insulin resistance(HOMA-IR)score (r = 0.194, P = 0.017); and fasting serum insulin (r = 0.167, P = 0.041) and IL-6 (r = 0.311, P < 0.001) concentrations. CONCLUSIONS Our results suggested that circulating sRAGE is independently risk factor for CRC, and also closely related to inflammation, dyslipidemia in type 2 diabetes patients.
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Affiliation(s)
- Xiaohai Zhou
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China
| | - Ning Lin
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China
| | - Mingjie Zhang
- Shanghai Jiahui International Hospital, 689 Guiping Road, Xuhui District, Shanghai, China
| | - Xiaoling Wang
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China
| | - Ye An
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China
| | - Peng Du
- Department of Colorectal Surgery, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China.
| | - Bo Li
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China.
| | - Hanbei Chen
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China.
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Carter P, Vithayathil M, Kar S, Potluri R, Mason AM, Larsson SC, Burgess S. Predicting the effect of statins on cancer risk using genetic variants from a Mendelian randomization study in the UK Biobank. eLife 2020; 9:57191. [PMID: 33046214 PMCID: PMC7553780 DOI: 10.7554/elife.57191] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 09/23/2020] [Indexed: 12/17/2022] Open
Abstract
Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. Here we assess the potential effect of statin therapy on cancer risk using evidence from human genetics. We obtained associations of lipid-related genetic variants with the risk of overall and 22 site-specific cancers for 367,703 individuals in the UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (odds ratio [OR] per one standard deviation decrease in low-density lipoprotein [LDL] cholesterol 0.76, 95% confidence interval [CI] 0.65-0.88, p=0.0003) but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically predicted LDL-cholesterol was not associated with overall cancer risk (OR per standard deviation increase 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.
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Affiliation(s)
- Paul Carter
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | | | - Siddhartha Kar
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.,Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Rahul Potluri
- ACALM Study Unit, Aston Medical School, Birmingham, United Kingdom
| | - Amy M Mason
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Susanna C Larsson
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Stephen Burgess
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.,MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom
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