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Zhu N, Zhao Y, Yan W, Wei L, Sang Q, Li J, Liu B, Yu B. Characterization of alternative splicing events and prognostic signatures in gastric cancer. Cancer Cell Int 2024; 24:167. [PMID: 38734676 PMCID: PMC11088037 DOI: 10.1186/s12935-024-03348-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 04/28/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND Accumulating evidences indicate that the specific alternative splicing (AS) events are linked to the occurrence and prognosis of gastric cancer (GC). Nevertheless, the impact of AS is still unclear and needed to further elucidation. METHODS The expression profile of GC and normal samples were downloaded from TCGA. AS events were achieved from SpliceSeq database. Cox regression together with LASSO analysis were employed to identify survival-associated AS events (SASEs) and calculate risk scores. PPI and pathway enrichment analysis were implemented to determine the function and pathways of these genes. Kaplan-Meier (K-M) analysis and Receiver Operating Characteristic Curves were used to evaluate the clinical significance of genes of SASEs. Q-PCR were applied to validate the hub genes on the survival prognosis in 47 GC samples. Drug sensitivity and immune cell infiltration analysis were conducted. RESULTS In total, 48 140 AS events in 10 610 genes from 361 GC and 31 normal samples were analyzed. Through univariate Cox regression, 855 SASEs in 763 genes were screened out. Further, these SASEs were analyzed by PPI and 17 hub genes were identified. Meanwhile, using Lasso and multivariate Cox regression analysis, 135 SASEs in 132 genes related to 7 AS forms were further screened and a GC prognostic model was constructed. K-M curves indicates that high-risk group has poorer prognosis. And the nomogram analysis on the basis of the multivariate Cox analysis was disclosed the interrelationships between 7 AS forms and clinical parameters in the model. Five key genes were then screened out by PPI analysis and Differential Expression Gene analysis based on TCGA and Combined-dataset, namely STAT3, RAD51B, SOCS2, POLE2 and TSR1. The expression levels of AS in STAT3, RAD51B, SOCS2, POLE2 and TSR1 were all significantly correlated with survival by qPCR verification. Nineteen drugs were sensitized to high-risk patients and eight immune cells showed significantly different infiltration between the STAD and normal groups. CONCLUSIONS In this research, the prognostic model constructed by SASEs can be applied to predict the prognosis of GC patients and the selected key genes are expected to become new biomarkers and therapeutical targets for GC treatment.
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Affiliation(s)
- Nan Zhu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yupeng Zhao
- Gastroenterological Surgery, The affiliated Wuxi No. 2, People's Hospital of Nanjing Medical University, Wuxi, 200240, China
| | - Wenjing Yan
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Lan Wei
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Qingqing Sang
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jianfang Li
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Bingya Liu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Beiqin Yu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Shekarriz R, Jabbari H, Alikhani R, Alizadeh-Navaei R, Hashemi-Soteh MB. Association between MUC1 rs4072037 polymorphism and Helicobacter pylori in patients with gastric cancer. CASPIAN JOURNAL OF INTERNAL MEDICINE 2024; 15:132-140. [PMID: 38463926 PMCID: PMC10921109 DOI: 10.22088/cjim.15.1.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 02/21/2023] [Accepted: 04/24/2023] [Indexed: 03/12/2024]
Abstract
Background The MUC1 gene encodes glycoproteins attached to cell membrane that play a protective role in gastric cancer and protect epithelial surfaces against external factors such as Helicobacter pylori. H. pylori infection can induce a cascade of innate and acquired immune responses in gastric mucosa. Relationship between rs4072037G>A polymorphism of MUC1 gene and increased susceptibility to H. pylori infection aimed to investigate in patients with gastric cancer in Mazandaran, northern Iran. Methods A case-control study was conducted on 99 patients with gastric cancer (H. pylori positive and negative) and 98 controls (H. pylori positive and negative) without gastric cancer (confirmed by pathological biopsy samples obtained during endoscopy). H. pylori infection was diagnosed by histological examination using Giemsa staining. Genomic DNA extracted from peripheral blood was analyzed by PCR-RFLP technique. Results Analysis of all genetic models showed no significant relationship between rs4072037G>A polymorphism and risk of gastric cancer (GC). The relationship between H. pylori infection and rs4072037G>A polymorphism showed an increased susceptibility to gastric cancer in both positive and negative H. pylori groups (including case and control groups). The genetic model of GA/GG and H. pylori- positive versus GA/GG and H. pylori-negative showed a significantly increased susceptibility to gastric cancer (OR=0.251, CI: 0.128-0.493, P=0.000). Conclusion These findings indicate that rs4072037G>A polymorphism may interact with H. pylori infection to increase the risk of GC.
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Affiliation(s)
- Ramin Shekarriz
- Department of Hematology and Oncology, Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hadi Jabbari
- Department of Internal Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Reza Alikhani
- Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Reza Alizadeh-Navaei
- Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Bagher Hashemi-Soteh
- Immunogenetics Research Center, Cell and Molecular Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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Nakanishi T, Willett J, Farjoun Y, Allen RJ, Guillen-Guio B, Adra D, Zhou S, Richards JB. Alternative splicing in lung influences COVID-19 severity and respiratory diseases. Nat Commun 2023; 14:6198. [PMID: 37794074 PMCID: PMC10550956 DOI: 10.1038/s41467-023-41912-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 09/21/2023] [Indexed: 10/06/2023] Open
Abstract
Alternative splicing generates functional diversity in isoforms, impacting immune response to infection. Here, we evaluate the causal role of alternative splicing in COVID-19 severity and susceptibility by applying two-sample Mendelian randomization to cis-splicing quantitative trait loci and the results from COVID-19 Host Genetics Initiative. We identify that alternative splicing in lung, rather than total expression of OAS1, ATP11A, DPP9 and NPNT, is associated with COVID-19 severity. MUC1 and PMF1 splicing is associated with COVID-19 susceptibility. Colocalization analyses support a shared genetic mechanism between COVID-19 severity with idiopathic pulmonary fibrosis at the ATP11A and DPP9 loci, and with chronic obstructive lung diseases at the NPNT locus. Last, we show that ATP11A, DPP9, NPNT, and MUC1 are highly expressed in lung alveolar epithelial cells, both in COVID-19 uninfected and infected samples. These findings clarify the importance of alternative splicing in lung for COVID-19 and respiratory diseases, providing isoform-based targets for drug discovery.
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Affiliation(s)
- Tomoko Nakanishi
- Department of Human Genetics, McGill University, Montréal, QC, Canada.
- Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
- Kyoto-McGill International Collaborative Program in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
- Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
- Research Fellow, Japan Society for the Promotion of Science, Tokyo, Japan.
| | - Julian Willett
- Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada
- Quantitative Life Sciences Program, McGill University, Montréal, Canada
- McGill Genome Centre, McGill University, Montréal, QC, Canada
| | - Yossi Farjoun
- Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada
- Five Prime Sciences Inc, Montréal, QC, Canada
| | - Richard J Allen
- Department of Population Health Sciences, University of Leicester, Leicester, United Kingdom
- National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Beatriz Guillen-Guio
- Department of Population Health Sciences, University of Leicester, Leicester, United Kingdom
- National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Darin Adra
- Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada
| | - Sirui Zhou
- Department of Human Genetics, McGill University, Montréal, QC, Canada
- Quantitative Life Sciences Program, McGill University, Montréal, Canada
- McGill Genome Centre, McGill University, Montréal, QC, Canada
| | - J Brent Richards
- Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
- Five Prime Sciences Inc, Montréal, QC, Canada.
- Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal, QC, Canada.
- Department of Twin Research, King's College London, London, UK.
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Nguyen NLT, Dang NDT, Vu QVAN, Dang AK, Ta TVAN. A Model for Gastric Cancer Risk Prediction Based on MUC1 Polymorphisms and Health-risk Behaviors in a Vietnamese Population. In Vivo 2023; 37:2347-2356. [PMID: 37652501 PMCID: PMC10500499 DOI: 10.21873/invivo.13339] [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: 06/03/2023] [Revised: 07/02/2023] [Accepted: 07/05/2023] [Indexed: 09/02/2023]
Abstract
BACKGROUND/AIM Although the expression of mucin 1(MUC1) and prostate stem cell antigen (PSCA) genes is correlated with gastric cancer development and progression, the utility of these two genes as biomarkers of gastric cancer prognosis still needs to be confirmed in clinical practice. This study aimed to develop a model predictive of gastric cancer that integrates several significant single nucleotide polymorphisms (SNPs) of MUC1 and PSCA genes, and some health-risk behavior factors in a Vietnamese population. PATIENTS AND METHODS A total of 302 patients with primary gastric carcinoma and 304 healthy persons were included in a case-control study. The generalized linear model was used with the profile of age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases, and the SNPs of MUC1 and PSCA. The prognostic value of the model was assessed by the area under a receiver operating characteristic curve (AUC) and Akaike Information Criterion (AIC) values. RESULTS In male participants, the final model, consisting of age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases and SNP MUC1 rs4072037, provided acceptable discrimination, with an AUC of 0.6374 and the lowest AIC value (539.53). In female participants, the predictive model including age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases, SNPs MUC1 rs4072037 and rs2070803 had an AUC of 0.6937 and AIC of 266.80. The calibration plots of the male model approximately fitted the ideal calibration line. CONCLUSION The predictive model based on age, sex, medical history, and genetic and health-risk behavior factors has a high potential in determining gastric cancer. Further studies that elucidate other genetic variants should be carried out to define high-risk gastric cancer groups and propose appropriate personalized prevention.
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Affiliation(s)
| | - Ngoc Dung Thi Dang
- Hanoi Medical University Hospital, Hanoi Medical University, Hanoi, Vietnam;
| | - Quy VAN Vu
- Hanoi Medical University Hospital, Hanoi Medical University, Hanoi, Vietnam
| | - Anh Kim Dang
- School of Preventive Medicine and Public Health, Hanoi Medical University, Hanoi, Vietnam
| | - Thanh-VAN Ta
- Hanoi Medical University Hospital, Hanoi Medical University, Hanoi, Vietnam;
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Azekawa S, Chubachi S, Asakura T, Namkoong H, Sato Y, Edahiro R, Lee H, Tanaka H, Otake S, Nakagawara K, Fukushima T, Watase M, Sakurai K, Kusumoto T, Masaki K, Kamata H, Ishii M, Hasegawa N, Okada Y, Koike R, Kitagawa Y, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K. Serum KL-6 levels predict clinical outcomes and are associated with MUC1 polymorphism in Japanese patients with COVID-19. BMJ Open Respir Res 2023; 10:10/1/e001625. [PMID: 37230764 DOI: 10.1136/bmjresp-2023-001625] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 05/17/2023] [Indexed: 05/27/2023] Open
Abstract
BACKGROUND Krebs von den Lungen-6 (KL-6) is a known biomarker for diagnosis and monitoring of interstitial lung diseases. However, the role of serum KL-6 and the mucin 1 (MUC1) variant (rs4072037) in COVID-19 outcomes remains to be elucidated. We aimed to evaluate the relationships among serum KL-6 levels, critical outcomes and the MUC1 variant in Japanese patients with COVID-19. METHODS This is a secondary analysis of a multicentre retrospective study using data from the Japan COVID-19 Task Force collected from February 2020 to November 2021, including 2226 patients with COVID-19 whose serum KL-6 levels were measured. An optimal serum KL-6 level cut-off to predict critical outcomes was determined and used for multivariable logistic regression analysis. Furthermore, the relationship among the allele dosage of the MUC1 variant, calculated from single nucleotide polymorphism typing data of genome-wide association studies using the imputation method, serum KL-6 levels and COVID-19 critical outcomes was evaluated. RESULTS Serum KL-6 levels were significantly higher in patients with COVID-19 with critical outcomes (511±442 U/mL) than those without (279±204 U/mL) (p<0.001). Serum KL-6 levels ≥304 U/mL independently predicted critical outcomes (adjusted OR (aOR) 3.47, 95% CI 2.44 to 4.95). Moreover, multivariable logistic regression analysis with age and sex indicated that the MUC1 variant was independently associated with increased serum KL-6 levels (aOR 0.24, 95% CI 0.28 to 0.32) but not significantly associated with critical outcomes (aOR 1.11, 95% CI 0.80 to 1.54). CONCLUSION Serum KL-6 levels predicted critical outcomes in Japanese patients with COVID-19 and were associated with the MUC1 variant. Therefore, serum KL-6 level is a potentially useful biomarker of critical COVID-19 outcomes.
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Affiliation(s)
- Shuhei Azekawa
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Shotaro Chubachi
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Takanori Asakura
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
- Department of Clinical Medicine (Laboratory of Bioregulatory Medicine), Kitasato University School of Pharmacy, Tokyo, Japan
- Department of Respiratory Medicine, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan
| | - Ho Namkoong
- Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan
| | - Yasunori Sato
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Ryuya Edahiro
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ho Lee
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Hiromu Tanaka
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Shiro Otake
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Kensuke Nakagawara
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Takahiro Fukushima
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Mayuko Watase
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Kaori Sakurai
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Tatsuya Kusumoto
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Katsunori Masaki
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Hirofumi Kamata
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Makoto Ishii
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine Faculty of Medicine, Nagoya, Japan
| | - Naoki Hasegawa
- Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan
| | - Yukinori Okada
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan
- Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
- Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Ryuji Koike
- Medical Innovation Promotion Center, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Akinori Kimura
- Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Seiya Imoto
- Division of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoru Miyano
- M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine Faculty of Medicine, Kyoto, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
| | - Koichi Fukunaga
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
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Risk Prediction for Gastric Cancer Using GWAS-Identifie Polymorphisms, Helicobacter pylori Infection and Lifestyle-Related Risk Factors in a Japanese Population. Cancers (Basel) 2021; 13:cancers13215525. [PMID: 34771687 PMCID: PMC8583059 DOI: 10.3390/cancers13215525] [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: 09/01/2021] [Revised: 10/27/2021] [Accepted: 10/30/2021] [Indexed: 11/18/2022] Open
Abstract
Simple Summary Gastric cancer remains the major cancer in Japan and worldwide. It is expected that practical intervention strategies for prevention, such as personalized approaches based on genetic risk models, will be developed. Here, we developed and validated a risk prediction model for gastric cancer using genetic, biological, and lifestyle-related risk factors. Results showed that the combination of selected GWAS-identified SNP polymorphisms and other predictors provided high discriminatory accuracy and good calibration in both the derivation and validation studies; however, the contribution of genetic factors to risk prediction was limited. The greatest contributor to risk prediction was ABCD classification (Helicobacter pylori infection-related factor). Abstract Background: As part of our efforts to develop practical intervention applications for cancer prevention, we investigated a risk prediction model for gastric cancer based on genetic, biological, and lifestyle-related risk factors. Methods: We conducted two independent age- and sex-matched case–control studies, the first for model derivation (696 cases and 1392 controls) and the second (795 and 795) for external validation. Using the derivation study data, we developed a prediction model by fitting a conditional logistic regression model using the predictors age, ABCD classification defined by H. pylori infection and gastric atrophy, smoking, alcohol consumption, fruit and vegetable intake, and 3 GWAS-identified polymorphisms. Performance was assessed with regard to discrimination (area under the curve (AUC)) and calibration (calibration plots and Hosmer–Lemeshow test). Results: A combination of selected GWAS-identified polymorphisms and the other predictors provided high discriminatory accuracy and good calibration in both the derivation and validation studies, with AUCs of 0.77 (95% confidence intervals: 0.75–0.79) and 0.78 (0.77–0.81), respectively. The calibration plots of both studies stayed close to the ideal calibration line. In the validation study, the environmental model (nongenetic model) was significantly more discriminative than the inclusive model, with an AUC value of 0.80 (0.77–0.82). Conclusion: The contribution of genetic factors to risk prediction was limited, and the ABCD classification (H. pylori infection-related factor) contributes most to risk prediction of gastric cancer.
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Pleiotropic Effects of Functional MUC1 Variants on Cardiometabolic, Renal, and Hematological Traits in the Taiwanese Population. Int J Mol Sci 2021; 22:ijms221910641. [PMID: 34638981 PMCID: PMC8509060 DOI: 10.3390/ijms221910641] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 09/09/2021] [Accepted: 09/27/2021] [Indexed: 12/27/2022] Open
Abstract
MUC1 is a transmembrane mucin involved in carcinogenesis and cell signaling. Functional MUC1 variants are associated with multiple metabolic and biochemical traits. This study investigated the association of functional MUC1 variants with MUC1 DNA methylation and various metabolic, biochemical, and hematological parameters. In total, 80,728 participants from the Taiwan Biobank were enrolled for association analysis using functional MUC1 variants and a nearby gene regional plot association study. A subgroup of 1686 participants was recruited for MUC1 DNA methylation analysis. After Bonferroni correction, we found that two MUC1 variants, rs4072037 and rs12411216, were significantly associated with waist circumference, systolic blood pressure, hemoglobin A1C, renal functional parameters (blood urea nitrogen, serum creatinine levels, and estimated glomerular filtration rate), albuminuria, hematocrit, hemoglobin, red blood cell count, serum uric acid level, and gout risk, with both favorable and unfavorable effects. Causal inference analysis revealed that the association between the variants and gout was partially dependent on the serum uric acid level. Both gene variants showed genome-wide significant associations with MUC1 gene-body methylation. Regional plot association analysis further revealed lead single-nucleotide polymorphisms situated at the nearby TRIM46-MUC1-THBS3-MTX1 gene region for the studied phenotypes. In conclusion, our data demonstrated the pleiotropic effects of MUC1 variants with novel associations for gout, red blood cell parameters, and MUC1 DNA methylation. These results provide further evidence in understanding the critical role of TRIM46-MUC1-THBS3-MTX1 gene region variants in the pathogenesis of cardiometabolic, renal, and hematological disorders.
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Vylet'al P, Kidd K, Ainsworth HC, Springer D, Vrbacká A, Přistoupilová A, Hughey RP, Alper SL, Lennon N, Harrison S, Harden M, Robins V, Taylor A, Martin L, Howard K, Bitar I, Langefeld CD, Barešová V, Hartmannová H, Hodaňová K, Zima T, Živná M, Kmoch S, Bleyer AJ. Plasma Mucin-1 (CA15-3) Levels in Autosomal Dominant Tubulointerstitial Kidney Disease due to MUC1 Mutations. Am J Nephrol 2021; 52:378-387. [PMID: 34098564 DOI: 10.1159/000515810] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/03/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Patients with ADTKD-MUC1 have one allele producing normal mucin-1 (MUC1) and one allele producing mutant MUC1, which remains intracellular. We hypothesized that ADTKD-MUC1 patients, who have only 1 secretory-competent wild-type MUC1 allele, should exhibit decreased plasma mucin-1 (MUC1) levels. To test this hypothesis, we repurposed the serum CA15-3 assay used to measure MUC1 in breast cancer to measure plasma MUC1 levels in ADTKD-MUC1. METHODS This cross-sectional study analyzed CA15-3 levels in a reference population of 6,850 individuals, in 85 individuals with ADTKD-MUC1, and in a control population including 135 individuals with ADTKD-UMOD and 114 healthy individuals. RESULTS Plasma CA15-3 levels (mean ± standard deviation) were 8.6 ± 4.3 U/mL in individuals with ADTKD-MUC1 and 14.6 ± 5.6 U/mL in controls (p < 0.001). While there was a significant difference in mean CA15-3 levels, there was substantial overlap between the 2 groups. Plasma CA15-3 levels were <5 U/mL in 22% of ADTKD-MUC1 patients, in 0/249 controls, and in 1% of the reference population. Plasma CA15-3 levels were >20 U/mL in 1/85 ADTKD-MUC1 patients, in 18% of control individuals, and in 25% of the reference population. Segregation of plasma CA15-3 levels by the rs4072037 genotype did not significantly improve differentiation between affected and unaffected individuals. CA15-3 levels were minimally affected by gender and estimated glomerular filtration rate. DISCUSSION/CONCLUSIONS Plasma CA15-3 levels in ADTKD-MUC1 patients are approximately 40% lower than levels in healthy individuals, though there is significant overlap between groups. Further investigations need to be performed to see if plasma CA15-3 levels would be useful in diagnosis, prognosis, or assessing response to new therapies in this disorder.
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Affiliation(s)
- Petr Vylet'al
- Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czechia
| | - Kendrah Kidd
- Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czechia
- Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Hannah C Ainsworth
- Division of Public Health Sciences, Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Drahomíra Springer
- Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and the First Faculty of Medicine of Charles University, Prague, Czechia
| | - Alena Vrbacká
- Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czechia
| | - Anna Přistoupilová
- Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czechia
| | - Rebecca P Hughey
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Seth L Alper
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Niall Lennon
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Steven Harrison
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Maegan Harden
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Victoria Robins
- Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Abbigail Taylor
- Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Lauren Martin
- Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Katrice Howard
- Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Ibrahim Bitar
- Biomedical Center and Institute of Microbiology, Faculty of Medicine in Pilsen of Charles University, Pilsen, Czechia
| | - Carl D Langefeld
- Division of Public Health Sciences, Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Veronika Barešová
- Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czechia
| | - Hana Hartmannová
- Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czechia
| | - Kateřina Hodaňová
- Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czechia
| | - Tomáš Zima
- Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and the First Faculty of Medicine of Charles University, Prague, Czechia
| | - Martina Živná
- Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czechia
| | - Stanislav Kmoch
- Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czechia
- Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Anthony J Bleyer
- Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czechia
- Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
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9
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Alikhani R, Taravati A, Hashemi-Soteh MB. Association of MUC1 5640G>A and PSCA 5057C>T polymorphisms with the risk of gastric cancer in Northern Iran. BMC MEDICAL GENETICS 2020; 21:148. [PMID: 32660489 PMCID: PMC7359498 DOI: 10.1186/s12881-020-01085-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 07/02/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Gastric cancer is one of the four most common cancer that causing death worldwide. Genome-Wide Association Studies (GWAS) have shown that genetic diversities MUC1 (Mucin 1) and PSCA (Prostate Stem Cell Antigen) genes are involved in gastric cancer. The aim of this study was avaluating the association of rs4072037G > A polymorphism in MUC1 and rs2294008 C > T in PSCA gene with risk of gastric cancer in northern Iran. METHODS DNA was extracted from 99 formalin fixed paraffin-embedded (FFPE) tissue samples of gastric cancer and 96 peripheral blood samples from healthy individuals (sex matched) as controls. Two desired polymorphisms, 5640G > A and 5057C > T for MUC1 and PSCA genes were genotyped using PCR-RFLP method. RESULTS The G allele at rs4072037 of MUC1 gene was associated with a significant decreased gastric cancer risk (OR = 0.507, 95% CI: 0.322-0.799, p = 0.003). A significant decreased risk of gastric cancer was observed in people with either AG vs. AA, AG + AA vs. GG and AA+GG vs. AG genotypes of MUC1 polymorphism (OR = 4.296, 95% CI: 1.190-15.517, p = 0.026), (OR = 3.726, 95% CI: 2.033-6.830, p = 0.0001) and (OR = 0.223, 95% CI: 0.120-0.413, p = 0.0001) respectively. Finally, there was no significant association between the PSCA 5057C > T polymorphism and risk of gastric cancer in all genetic models. CONCLUSION Results indicated that the MUC1 5640G > A polymorphism may have protective effect for gastric cancer in the Northern Iran population and could be considered as a potential molecular marker in gastric cancer.
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Affiliation(s)
- Reza Alikhani
- Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran
| | - Ali Taravati
- Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran
| | - Mohammad Bagher Hashemi-Soteh
- Immunogenetic Research center, Molecular and Cell Biology Research Center, Medical Faculty, Mazandaran University of Medical Sciences, Sari, Mazandaran, 48166-13485, Iran.
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10
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Kim BS, Lee I, Yook JH, Song K, Kim BS. Association between the MUC1 rs4072037 Polymorphism and Risk of Gastric Cancer and Clinical Outcomes. J Gastric Cancer 2020; 20:127-138. [PMID: 32595997 PMCID: PMC7311214 DOI: 10.5230/jgc.2020.20.e11] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 02/29/2020] [Accepted: 03/08/2020] [Indexed: 12/11/2022] Open
Abstract
Purpose Mucin 1 (MUC1) was identified as a gastric cancer (GC) susceptibility gene by genome-wide association studies in Asians and candidate gene studies in Europeans. This study aimed to investigate the association between the MUC1 rs4072037 polymorphism and GC in terms of the Lauren classification and long-term clinical outcomes. Materials and Methods A total of 803 patients with GC and 816 unrelated healthy controls were enrolled in the study. The association between the MUC1 rs4072037 variant and GC histological types and clinical outcomes, including tumor recurrence and prognosis was investigated. Results The major A allele of rs4072037 was associated with increased GC risk (P<0.05). In subtype analysis, the association was most significant for diffuse-type GC (P<0.05) and in a dominant model (P<0.05), whereas there was no association with intestinal-type GC (P>0.05). Cox proportional hazards analysis revealed the heterozygote AG rs4072037 allele as an independent risk factor influencing tumor recurrence and disease-related death in diffuse-type GC (P<0.05). but not in intestinal-type GC (P>0.05). Conclusions The exonic single nucleotide polymorphism rs4072037 in MUC1 was associated with diffuse-type GC and was an independent risk factor influencing tumor recurrence and disease-related death in diffuse-type GC.
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Affiliation(s)
- Beom Su Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Inchul Lee
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong Hwan Yook
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyuyoung Song
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
| | - Byung-Sik Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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11
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Ma G, Liu H, Du M, Zhang G, Lin Y, Ge Y, Wang M, Jin G, Zhao Q, Chu H, Gong W, Zhang Z. A genetic variation in the CpG island of pseudogene GBAP1 promoter is associated with gastric cancer susceptibility. Cancer 2019; 125:2465-2473. [PMID: 30951202 DOI: 10.1002/cncr.32081] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 02/22/2019] [Accepted: 02/27/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND Previous genome-wide association studies (GWASs) have identified that several single nucleotide polymorphisms (SNPs) are implicated in gastric cancer (GC) risk. However, the multiple statistical comparisons of GWASs may reject some true biological positives with subthreshold P values. METHODS This study annotated the genomic locations of all CpG islands in the genome using the Encyclopedia of DNA Elements (ENCODE). The SNPs in the regions were then genotyped using the Illumina 660W Quad chip. The effects of the prominent variations on GC risk were further confirmed in the other independent cohorts. RESULTS SNP rs2990245, which is located in the promoter of pseudogene GBAP1, was associated with GC risk using GWASs data. An additional cohort of 1275 GC patients and 1424 controls validated that individuals with the CC genotype had a 62% decreased risk of GC compared with those who carried the TT genotype (P = 2.01E-04) in the codominant model. The significant association was observed in the additive, dominant, and recessive models. A meta-analysis combining the results from the GWASs and replication studies revealed that rs2990245 was significantly associated with decreased GC risk (P = 5.59E-12). Importantly, rs2990245 can regulate the expression of GBAP1 by influencing the methylation status of the GBAP1 promoter. GBAP1 can act as a competing endogenous RNA by binding competitively with micro-RNA-212-3p and then promoting GBA expression. CONCLUSION rs2990245 is significantly associated with a decreased risk of GC. Pseudogene GBAP1 contributes to the development and progression of GC by sequestering the miR-212-3p from binding to GBA.
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Affiliation(s)
- Gaoxiang Ma
- Department of Environmental Genomics, Center for Global Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.,School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Hanting Liu
- Department of Environmental Genomics, Center for Global Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Mulong Du
- Department of Environmental Genomics, Center for Global Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.,Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Gang Zhang
- Department of Environmental Genomics, Center for Global Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yadi Lin
- Department of Environmental Genomics, Center for Global Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yuqiu Ge
- Department of Environmental Genomics, Center for Global Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Meilin Wang
- Department of Environmental Genomics, Center for Global Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Guangfu Jin
- Department of Epidemiology and Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qinghong Zhao
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haiyan Chu
- Department of Environmental Genomics, Center for Global Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Weida Gong
- Department of General Surgery, Yixing Cancer Hospital, Yixing, China
| | - Zhengdong Zhang
- Department of Environmental Genomics, Center for Global Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
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12
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Lott PC, Carvajal-Carmona LG. Resolving gastric cancer aetiology: an update in genetic predisposition. Lancet Gastroenterol Hepatol 2018; 3:874-883. [PMID: 30507471 PMCID: PMC6500447 DOI: 10.1016/s2468-1253(18)30237-1] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/06/2018] [Accepted: 07/16/2018] [Indexed: 12/15/2022]
Abstract
Every year gastric cancer accounts for nearly 1 million new cases and more than 720 000 deaths worldwide. Prognosis is dismal because most patients are diagnosed with advanced disease; as such, gastric cancer outcomes will benefit from better methods for identification of at-risk individuals that can be targeted for early detection. One approach to targeting high-risk populations is to identify individuals who are genetically predisposed to gastric cancer, as up to 15% of all patients report family history of the disease. On the basis of clinical manifestations, three gastric cancer syndromes have been described, but the diagnosis of some of these syndromes is suboptimal and could benefit from genetic information. Over the past decade, genome-wide association and next-generation sequencing studies have identified several low penetrance variants and high-risk genes, considerably increasing our understanding of inherited gastric cancer predisposition. From these studies, PALB2 has emerged as a new familial gastric cancer gene. Furthermore, genetic analyses in patients with sporadic gastric cancer suggest that more than 10% of all cases have pathogenic mutations, a finding of great importance for cancer aetiology. In this Review, we summarise the role of genetics in gastric cancer aetiology and the implications of genetics findings for the prevention of this malignancy.
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Affiliation(s)
- Paul C Lott
- Genome Center, School of Medicine, University of California at Davis, Davis, CA, USA
| | - Luis G Carvajal-Carmona
- Genome Center, School of Medicine, University of California at Davis, Davis, CA, USA; Population Sciences and Cancer Health Disparities Program, UC Davis Comprehensive Cancer Center, School of Medicine, University of California at Davis, Davis, CA, USA; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Davis, CA, USA.
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13
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Kumar S, Cruz E, Joshi S, Patel A, Jahan R, Batra SK, Jain M. Genetic variants of mucins: unexplored conundrum. Carcinogenesis 2017; 38:671-679. [PMID: 27838635 DOI: 10.1093/carcin/bgw120] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 11/10/2016] [Indexed: 12/12/2022] Open
Abstract
Alternative gene splicing, occurring ubiquitously in multicellular organisms can produce several protein isoforms with putatively different functions. The enormously extended genomic structure of mucin genes characterized by the presence of multiple exons encoding various domains may result in functionally diverse repertoire of mucin proteins due to alternative splicing. Splice variants (Svs) and mutations in mucin genes have been observed in various cancers and shown to participate in cancer progression and metastasis. Although several mucin Svs have been identified, their potential functions remain largely unexplored with the exception of the Svs of MUC1 and MUC4. A few studies have examined the expression of MUC1 and MUC4 Svs in cancer and indicated their potential involvement in promoting cancer cell proliferation, invasion, migration, angiogenesis and inflammation. Herein we review the current understanding of mucin Svs in cancer and inflammation and discuss the potential impact of splicing in generating a functionally diverse repertoire of mucin gene products. We also performed mutational analysis of mucin genes across five major cancer types in International Cancer Genome Consortium database and found unequal mutational rates across the panel of cancer-associated mucins. Although the functional role of mucins in the pathobiology of various malignancies and their utility as diagnostic and therapeutic targets remain undisputed, these attributes need to be reevaluated in light of the potentially unique functions of disease-specific genetic variants of mucins. Thus, the expressional and functional characterization of the genetic variants of mucins may provide avenues to fully exploit their potential as novel biomarkers and therapeutic targets.
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Affiliation(s)
- Sushil Kumar
- Department of Biochemistry and Molecular Biology
| | - Eric Cruz
- Department of Biochemistry and Molecular Biology
| | | | - Asish Patel
- Department of Biochemistry and Molecular Biology
| | - Rahat Jahan
- Department of Biochemistry and Molecular Biology
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology.,Eppley Institute for Research in Cancer and Allied Diseases.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
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14
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Ye Y, Yang C, Xu L, Fang D. MUC1 rs4072037 polymorphism is associated with decreased risk of gastric cancer: a meta-analysis. Int J Biol Markers 2017; 32:e284-e290. [PMID: 28561882 DOI: 10.5301/ijbm.5000270] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Several studies have recently investigated the association between mucin 1 (MUC1) rs4072037 polymorphism and gastric cancer (GC) risk, but with conflicting results. The aim of this meta-analysis was to evaluate the association between MUC1 rs4072037 polymorphism and GC risk. METHODS A comprehensive database search of PubMed, Elsevier, Embase and China National Knowledge Infrastructure (CNKI) databases was performed to identify relevant studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of any association. RESULTS A total of 12 papers containing 18 studies were included in this meta-analysis, involving 12,373 cases and 15,008 controls. Our data suggested that rs4072037 polymorphism was associated with a decreased risk of GC. Stratification analyses of ethnicity indicated that rs4072037 decreased the risk of GC among white populations, but no significant relationship was observed among Asian populations. No significant associations were observed in subgroups of Lauren classification (intestinal or diffuse) and anatomical classification (cardia or non-cardia). CONCLUSIONS In conclusion, this meta-analysis suggested that rs4245739 polymorphism in the MUC1 gene may play a pivotal role in the pathogenesis of GC, especially for white populations.
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Affiliation(s)
- Yu Ye
- Department of General Surgery, Hang Zhou Red Cross Hospital, Hangzhou, Zhejiang - PR China
| | - Chong Yang
- Department of General Surgery, Hang Zhou Red Cross Hospital, Hangzhou, Zhejiang - PR China
| | - Lei Xu
- Department of Digestion, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang - PR China
| | - Dilong Fang
- Department of General Surgery, Hang Zhou Red Cross Hospital, Hangzhou, Zhejiang - PR China
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15
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Evans CM, Fingerlin TE, Schwarz MI, Lynch D, Kurche J, Warg L, Yang IV, Schwartz DA. Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways. Physiol Rev 2017; 96:1567-91. [PMID: 27630174 PMCID: PMC5243224 DOI: 10.1152/physrev.00004.2016] [Citation(s) in RCA: 159] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants in at least 11 novel loci. We have previously found that 1) a common gain-of-function promoter variant in MUC5B rs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts. Based on these considerations, we hypothesize that excessive production of MUC5B either enhances injury due to reduced mucociliary clearance or impedes repair consequent to disruption of normal regenerative mechanisms in the distal lung. In aggregate, these novel considerations should have broad impact, resulting in specific etiologic targets, early detection of disease, and novel biologic pathways for use in the design of future intervention, prevention, and mechanistic studies of IPF.
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Affiliation(s)
- Christopher M Evans
- Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, Colorado; National Jewish Health, Denver, Colorado; and Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, Colorado
| | - Tasha E Fingerlin
- Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, Colorado; National Jewish Health, Denver, Colorado; and Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, Colorado
| | - Marvin I Schwarz
- Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, Colorado; National Jewish Health, Denver, Colorado; and Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, Colorado
| | - David Lynch
- Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, Colorado; National Jewish Health, Denver, Colorado; and Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, Colorado
| | - Jonathan Kurche
- Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, Colorado; National Jewish Health, Denver, Colorado; and Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, Colorado
| | - Laura Warg
- Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, Colorado; National Jewish Health, Denver, Colorado; and Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, Colorado
| | - Ivana V Yang
- Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, Colorado; National Jewish Health, Denver, Colorado; and Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, Colorado
| | - David A Schwartz
- Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, Colorado; National Jewish Health, Denver, Colorado; and Department of Immunology, University of Colorado Denver, School of Medicine, Aurora, Colorado
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16
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Li Y, Yuan Y. Alternative RNA splicing and gastric cancer. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2016; 773:263-273. [PMID: 28927534 DOI: 10.1016/j.mrrev.2016.07.011] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 07/06/2016] [Accepted: 07/28/2016] [Indexed: 02/07/2023]
Abstract
Alternative splicing (AS) linked to diseases, especially to tumors. Recently, more and more studies focused on the relationship between AS and gastric cancer (GC). This review surveyed the hot topic from four aspects: First, the common types of AS in cancer, including exon skipping, intron retention, mutually exclusive exon, alternative 5 ' or 3' splice site, alternative first or last exon and alternative 3' untranslated regions. Second, basic mechanisms of AS and its relationship with cancer. RNA splicing in eukaryotes follows the GT-AG rule by both cis-elements and trans-acting factors regulatory. Through RNA splicing, different proteins with different forms and functions can be produced and may be associated with carcinogenesis. Third, AS types of GC-related genes and their splicing variants. In this paper, we listed 10 common genes with AS and illustrated its possible molecular mechanisms owing to genetic variation (mutation and /or polymorphism). Fourth, the splicing variants of GC-associated genes and gastric carcinogenesis, invasion and metastasis. Many studies have found that the different splicing variants of the same gene are differentially expressed in GC and its precancerous diseases, suggesting AS has important implications in GC development. Taking together, this review highlighted the role of AS and splicing variants in the process of GC. We hope that this is not only beneficial to advances in the study field of GC, but also can provide valuable information to other similar tumor research.Although we already know some gene splicing and splicing variants play an important role in the development of GC, but many phenomena and mechanisms are still unknown. For example, how the tumor microenvironment and signal transduction pathway effect the forming and function of AS? Unfortunately, this review did not cover the contents because the current study is limited. It is no doubt that clarifying the phenomena and mechanisms of these unknown may help to reveal the relationship of AS with complex tumor genetic variation and the occurrence and development of tumors.
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Affiliation(s)
- Ying Li
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China.
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17
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Bonella F, Long X, Ohshimo S, Horimasu Y, Griese M, Guzman J, Kohno N, Costabel U. MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis. Orphanet J Rare Dis 2016; 11:48. [PMID: 27108412 PMCID: PMC4841967 DOI: 10.1186/s13023-016-0430-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 04/17/2016] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND KL-6, a human MUC1 mucin, is a sensitive biomarker for interstitial lung diseases including pulmonary alveolar proteinosis (PAP). A correlation between MUC1 gene single nucleotide polymorphism (SNP) rs4072037 genotype and serum KL-6 levels has been reported. This study was aimed at investigating the correlation between MUC1 SNP genotype, severity of disease and disease outcome in PAP. METHODS Twenty four patients with PAP and 30 healthy volunteers were studied. MUC1 rs4072037 was detected by using a real-time polymerase chain reaction (RT-PCR). Genotyping was performed by pyrosequencing. KL-6 levels were measured in serum by Nanopia KL-6 assay (SEKISUI Diagnostics). RESULTS The frequency of MUC1 rs4072037 alleles was significantly different between PAP patients and healthy volunteers (PAP, A/A 46%, A/G 54%, G/G 0%; healthy controls, A/A 30%, A/G 40%, G/G 30%; p = 0.013). Serum KL-6 levels were significantly higher in PAP patients than in controls (p < 0.0001), and significantly higher in PAP patients with A/A genotype than in those with A/G genotype (p = 0.007). Patients with A/A genotype had higher alveolar-arterial oxygen difference (A-aDO2) and lower DLco compared to those with A/G genotype (p = 0.027 and p = 0.012, respectively). Multivariate analysis, Kaplan-Meier analysis and C statistics showed that the rs4072037 A/A genotype was associated with higher rate of disease progression (HR: 5.557, p = 0.014). CONCLUSIONS MUC1 rs4072037 A/A genotype is associated with more severe pulmonary dysfunction and a higher rate of disease progression in PAP patients.
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Affiliation(s)
- Francesco Bonella
- Interstitial and Rare Lung Disease Unit, Ruhrlandklinik, University of Duisburg-Essen, 45239, Essen, Germany.
| | - Xiaoping Long
- Interstitial and Rare Lung Disease Unit, Ruhrlandklinik, University of Duisburg-Essen, 45239, Essen, Germany
- Department of Respiratory Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan, P. R China
| | - Shinichiro Ohshimo
- Department of Emergency and Critical Care Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
- Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasushi Horimasu
- Department of Emergency and Critical Care Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Matthias Griese
- Dr. von Haunersches Kinderspital, University of Munich, Munich, Germany
| | - Josune Guzman
- General and Experimental Pathology, Ruhr University, Bochum, Germany
| | - Nobuoki Kohno
- Department of Emergency and Critical Care Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Ulrich Costabel
- Interstitial and Rare Lung Disease Unit, Ruhrlandklinik, University of Duisburg-Essen, 45239, Essen, Germany
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18
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Qiu LX, Hua RX, Cheng L, He J, Wang MY, Zhou F, Zhu XD, Sun MH, Zhou XY, Li J, Wang YN, Yang YJ, Wang JC, Jin L, Guo WJ, Wei QY. Genetic variant rs4072037 of MUC1 and gastric cancer risk in an Eastern Chinese population. Oncotarget 2016; 7:15930-15936. [PMID: 26910281 PMCID: PMC4941287 DOI: 10.18632/oncotarget.7527] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Accepted: 12/31/1969] [Indexed: 02/07/2023] Open
Abstract
Published data on the association between the MUC1 rs4072037A > G polymorphism and gastric cancer (GCa) risk were inconclusive. To derive a more precise estimation of the association, we conducted a large GCa study of 1,124 cases and 1,192 controls to confirm this association in an Eastern Chinese population. Our results showed that the G allele was strongly associated with a decreased GCa risk in the study population [GG vs. AA, odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.31-0.73; AG/GG vs. AA, OR = 0.82, 95% CI = 0.68-0.99; GG vs. AA/AG, OR = 0.48, 95% CI = 0.32-0.74]. These associations remained significant in subgroups of age, tumor site, drinking and smoking status. Moreover, this association was supported by an additional meta-analysis of published studies. In summary, these results suggest that the MUC1 rs4072037G allele may be a low-penetrating protection factor for GCa risk in Chinese populations.
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Affiliation(s)
- Li-Xin Qiu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Rui-Xi Hua
- Department of Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Lei Cheng
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Meng-Yun Wang
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Fei Zhou
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiao-Dong Zhu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Meng-Hong Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiao-Yan Zhou
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jin Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ya-Nong Wang
- Department of Gastric Cancer and Soft Tissue Sarcoma Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ya-Jun Yang
- Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Jiu-Cun Wang
- Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Li Jin
- Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Wei-Jian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qing-Yi Wei
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- Duke Cancer Institute, Duke University Medical Center and Department of Medicine, Duke University School of Medicine, Durham, NC, USA
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Wen R, Gao F, Zhou CJ, Jia YB. Polymorphisms in mucin genes in the development of gastric cancer. World J Gastrointest Oncol 2015; 7:328-337. [PMID: 26600932 PMCID: PMC4644855 DOI: 10.4251/wjgo.v7.i11.328] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 07/01/2015] [Accepted: 09/07/2015] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. In areas of high prevalence, such as Japan, South Korea and China, most cases of GC are related to Helicobacter pylori (H. pylori), which involves well-characterized sequential stages, including infection, atrophic gastritis, intestinal metaplasia, dysplasia, and GC. Mucins are the most abundant high-molecular-weight glycoproteins in mucus, which is the first line of defense and plays a major role in blocking pathogenic factors. Normal gastric mucosa shows expression of MUC1, MUC5AC and MUC6 that is specific to cell type. However, the specific pattern of MUC1, MUC5AC and MUC6 expression is changed in gastric carcinogenesis, accompanied by de novo expression of secreted MUC2. Recent studies have provided evidence that variations in these mucin genes affect many steps of GC development, such as H. pylori infection, and gastric precancerous lesions. In this review, we focus on studies of the association between polymorphisms in mucin genes and development of GC. This information should be helpful for the early detection, surveillance, and treatment of GC.
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Nuclear localization of MUC1 extracellular domain in breast, head and neck, and colon cancer. Int J Biol Markers 2015; 30:e294-300. [DOI: 10.5301/jbm.5000147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2015] [Indexed: 01/10/2023]
Abstract
Background The glycoprotein MUC1 is overexpressed and underglycosylated in cancer cells. MUC1 is translated as a single polypeptide that undergoes autocleavage into 2 subunits (the extracellular domain and the cytoplasmic tail), and forms a stable heterodimer at the apical membrane of normal epithelial cells. The MUC1 cytoplasmic tail localizes to the cytoplasm of transformed cells and is targeted to the nucleus. Aims To study the expression of the MUC1 extracellular subunit in cell nuclei of neoplastic breast, head and neck, and colon samples. Materials and Methods 330 primary tumor samples were analyzed: 166 invasive breast carcinomas, 127 head and neck tumors, and 47 colon tumors; 10 benign breast disease (BBD) and 40 normal specimens were also included. A standard immunohistochemical method with antigen retrieval was performed. Nuclear fractions from tissue homogenates and breast cancer cell lines (ZR-75, MDA-MB-231, MCF7, and T47D) were obtained and analyzed by Western blotting (WB). The anti-MUC1 extracellular subunit monoclonal antibody HMFG1 was used for immunohistochemistry. Results 37/166 breast cancer specimens, 5/127 head and neck cancer specimens, 2/47 colon cancer samples, and 3/10 BBD samples showed immunohistochemical staining at the nuclear level. No nuclear reaction was detected in normal samples. By WB, breast and colon cancer purified nuclear fractions showed reactivity at 200 kDa in 3/30 breast and 3/20 colon cancer samples as well as purified nuclear fractions obtained from breast cancer cell lines. Conclusions This study shows that the MUC1 extracellular domain might be translocated to the cell nucleus in breast, head and neck, and colon cancer as well as BBD.
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Felipe AV, Oliveira J, Chang PYJ, Moraes AADFS, da Silva TD, Tucci-Viegas VM, Forones NM. RNA interference: a promising therapy for gastric cancer. Asian Pac J Cancer Prev 2015; 15:5509-15. [PMID: 25081656 DOI: 10.7314/apjcp.2014.15.14.5509] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Gastric cancer (GC) remains a virtually incurable disease when metastatic and requires early screening tools for detection of early tumor stages. Therefore, finding effective strategies for prevention or recurrence of GC has become a major overall initiative. RNA-interference (RNAi) is an innovative technique that can significantly regulate the expression of oncogenes involved in gastric carcinogenesis, thus constituting a promising epigenetic approach to GC therapy. This review presents recent advances concerning the promising biomolecular mechanism of RNAi for GC treatment.
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Affiliation(s)
- Aledson Vitor Felipe
- Department of Medicine, Gastroenterology Division, Federal University of Sao Paulo, Sao Paulo, Brazil E-mail :
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22
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Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet 2015; 47:906-10. [PMID: 26098866 DOI: 10.1038/ng.3342] [Citation(s) in RCA: 126] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 05/29/2015] [Indexed: 12/18/2022]
Abstract
Gastric cancer is a serious health problem worldwide, with particularly high prevalence in eastern Asia. Genome-wide association studies (GWAS) in Asian populations have identified several loci that associate with gastric cancer risk. Here we report a GWAS of gastric cancer in a European population, using information on 2,500 population-based gastric cancer cases and 205,652 controls. We found a new gastric cancer association with loss-of-function mutations in ATM (gene test, P = 8.0 × 10(-12); odds ratio (OR) = 4.74). The combination of the loss-of-function variants p.Gln852*, p.Ser644* and p.Tyr103* (combined minor allele frequency (MAF) = 0.3%) also associates with pancreatic and prostate cancers (OR = 3.81 and 2.18, respectively) and gives an indication of risk of breast and colorectal cancers (OR = 1.82 and 1.97, respectively). Cancers in those carrying loss-of-function ATM mutations are diagnosed at a significantly earlier age than in non-carriers. Our results confirm an association between gastric cancer in Europeans and three loci previously reported in Asians, MUC1, PRKAA1 and PSCA, refine the association signal at PRKAA1 and support a pathogenic role for the tandem repeat identified in MUC1.
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Zhang B, Hao GY, Gao F, Zhang JZ, Zhou CJ, Zhou LS, Wang Y, Jia YB. Lack of association of common polymorphisms in MUC1 gene with H. pylori infection and non-cardia gastric cancer risk in a Chinese population. Asian Pac J Cancer Prev 2015; 14:7355-8. [PMID: 24460302 DOI: 10.7314/apjcp.2013.14.12.7355] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Several lines of evidence support the notion that MUC1 is often aberrantly expressed in gastric cancer, and it is a ligand for Helicobacter pylori. Genetic variation in MUC1 gene may confer susceptibility to H. pylori infection and gastric cancer. We assessed the association of common polymorphisms in MUC1 gene with H. pylori infection and non-cardia gastric cancer using an LD-based tag SNP approach in north-western Chinese Han population. A total of four SNPs were successfully genotyped among 288 patients with non-cardia gastric cancer and 281 age- and sex-matched controls. None of the tested SNPs was associated with H. pylori infection. SNP rs9426886 was associated with a decreased risk of non-cardia gastric cancer, but lost significance after adjustment for multiple testing. Overall, our data indicated that common genetic variations in MUC1 gene might not make a major contribution to the risk of H. pylori infection and non-cardia gastric cancer in our studied population.
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Affiliation(s)
- Bin Zhang
- School of Basic Medicine, Baotou Medical College, Baotou, China E-mail :
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Abstract
Gastric cancer remains highly prevalent and accounts for a notable proportion of global cancer mortality. This cancer is also associated with poor survival rates. Understanding the genetic basis of gastric cancer will offer insights into its pathogenesis, help identify new biomarkers and novel treatment targets, aid prognostication and could be central to developing individualized treatment strategies in the future. An inherited component contributes to <3% of gastric cancers; the majority of genetic changes associated with gastric cancer are acquired. Over the past few decades, advances in technology and high-throughput analysis have improved understanding of the molecular aspects of the pathogenesis of gastric cancer. These aspects are multifaceted and heterogeneous and represent a wide spectrum of several key genetic influences, such as chromosomal instability, microsatellite instability, changes in microRNA profile, somatic gene mutations or functional single nucleotide polymorphisms. These genetic aspects of the pathogenesis of gastric cancer will be addressed in this Review.
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Affiliation(s)
- Mairi H McLean
- National Cancer Institute, Laboratory of Molecular Immunoregulation, Cancer &Inflammation Program, 1050 Boyles Street, Frederick, MD 21702-1201, USA
| | - Emad M El-Omar
- Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB51 5ER, UK
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Liu X, Wang Z, Zhang X, Chang J, Tang W, Gan L, Wu Z, Li J. MUC1 gene polymorphism rs4072037 and susceptibility to gastric cancer: a meta-analysis. SPRINGERPLUS 2014; 3:599. [PMID: 25332893 PMCID: PMC4198476 DOI: 10.1186/2193-1801-3-599] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 10/06/2014] [Indexed: 12/14/2022]
Abstract
The association between MUC1 polymorphism rs4072037 and the risk of gastric cancer has been described in several studies. However, these studies yielded inconsistent results, especially in different pathological type of gastric cancer. Therefore, we performed this meta-analysis to evaluate the relationship between MUC1 gene polymorphism and gastric cancer susceptibility. A comprehensive database search was performed to identify eligible studies. Odds ratios with 95% confidence intervals were calculated to assess the strength of the association between MUC1 rs4072037 and risk of gastric cancer. Subgroup analyses, publication bias, and sensitivity analyses were also conducted. PubMed, EMBASE, Web of Science and CNKI databases were systematically searched to identify relevant studies. A total of 9 studies (12 datasets) were included in the meta-analysis including 10,410 cases and 11,437 controls. Overall, the G allele at rs4072037 of MUC1 gene was associated with a significant decreased gastric cancer risk (OR=0.70, 95% CI: 0.64-0.76). The association was significant in both anatomic location and pathological subtype subgroup analyses. However, the association was detected in Asian rather than Caucasian. Our findings demonstrate that the presence of the G allele at rs4072037 of the MUC1 gene may contribute to protection against gastric cancer in Asian. Further large studies of multiethnic groups are needed to validate these findings.
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Affiliation(s)
- Xinyang Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 PR China
| | - Zhichao Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Xiaowei Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 PR China
| | - Jinjia Chang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 PR China
| | - Wenbo Tang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 PR China
| | - Lu Gan
- Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 PR China
| | - Zheng Wu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 PR China
| | - Jin Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 PR China
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Saeki N, Sakamoto H, Yoshida T. Mucin 1 gene (MUC1) and gastric-cancer susceptibility. Int J Mol Sci 2014; 15:7958-73. [PMID: 24810688 PMCID: PMC4057712 DOI: 10.3390/ijms15057958] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 04/11/2014] [Accepted: 04/21/2014] [Indexed: 12/22/2022] Open
Abstract
Gastric cancer (GC) is one of the major malignant diseases worldwide, especially in Asia. It is classified into intestinal and diffuse types. While the intestinal-type GC (IGC) is almost certainly caused by Helicobacter pylori (HP) infection, its role in the diffuse-type GC (DGC) appears limited. Recently, genome-wide association studies (GWAS) on Japanese and Chinese populations identified chromosome 1q22 as a GC susceptibility locus which harbors mucin 1 gene (MUC1) encoding a cell membrane-bound mucin protein. MUC1 has been known as an oncogene with an anti-apoptotic function in cancer cells; however, in normal gastric mucosa, it is anticipated that the mucin 1 protein has a role in protecting gastric epithelial cells from a variety of external insults which cause inflammation and carcinogenesis. HP infection is the most definite insult leading to GC, and a protective function of mucin 1 protein has been suggested by studies on Muc1 knocked-out mice.
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Affiliation(s)
- Norihisa Saeki
- Division of Genetics, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
| | - Hiromi Sakamoto
- Division of Genetics, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
| | - Teruhiko Yoshida
- Division of Genetics, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
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Duan F, Song C, Dai L, Cui S, Zhang X, Zhao X. The effect of MUC1 rs4072037 functional polymorphism on cancer susceptibility: evidence from published studies. PLoS One 2014; 9:e95651. [PMID: 24755768 PMCID: PMC3995803 DOI: 10.1371/journal.pone.0095651] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 03/10/2014] [Indexed: 12/25/2022] Open
Abstract
Genome-wide association studies have identified a susceptibility variation MUC1 rs4072037 for gastric cancer in Chinese population. Subsequent case-control studies have reported this association in other populations. However, the results remain controversial and ambiguous. The aim of this study is to provide a precise quantification for the association between MUC1 rs4072037 variation and the risk of cancer. We performed pooled analysis of 10 case-control designed studies including 4,220 cases and 6,384 controls. Odds ratios (OR) and 95% confidence interval (95%CI) were calculated to assess strength of association in overall studies and in subgroup analysis stratified by ethnicity and cancer types. All statistical analyses were performed by Manager 5.0 and Stata 12.0 software. Overall, the MUC1 rs4072037 polymorphism was associated with risk of cancer in all genetic models (G vs A: OR = 0.71, 95%CI: 0.63-0.80, p<0.01; GA vs AA: OR = 0.61, 95%CI:0.55-0.67, p<0.01; GG vs AA: OR = 0.58, 95%CI: 0.47-0.71, p<0.01; AG+AA vs GG: OR = 0.60, 95%CI: 0.55-0.60, p<0.01; GG vs AG+AA: OR = 0.70, 95%CI: 0.58-0.85, p<0.01). Further, subgroup analysis based on ethnicity suggested MUC1 rs4072037 polymorphism had a subtly reduced cancer risk among Asian population, and stratified analysis by cancer types showed significantly decreased risk of gastric cancer in all genetic models. In conclusion, MUC1 rs4072037 polymorphism may be used as potential biomarker for cancer susceptibility particularly for gastric cancer and for Asian population.
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Affiliation(s)
- Fujiao Duan
- Department of Hospital Infection Management, Affiliated Tumor Hospital of Zhengzhou University, Henan Tumor Hospital, Zhengzhou, Henan, China
| | - Chunhua Song
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, Henan, China
| | - Liping Dai
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, Henan, China
| | - Shuli Cui
- College of Professional Study, Northeastern University, Boston, Massachusetts, United States of America
| | - Xiaoqin Zhang
- Department of Hospital Infection Management, Affiliated Tumor Hospital of Zhengzhou University, Henan Tumor Hospital, Zhengzhou, Henan, China
| | - Xia Zhao
- Department of Hospital Infection Management, Affiliated Tumor Hospital of Zhengzhou University, Henan Tumor Hospital, Zhengzhou, Henan, China
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Williams KA, Terry KL, Tworoger SS, Vitonis AF, Titus LJ, Cramer DW. Polymorphisms of MUC16 (CA125) and MUC1 (CA15.3) in relation to ovarian cancer risk and survival. PLoS One 2014; 9:e88334. [PMID: 24551091 PMCID: PMC3923771 DOI: 10.1371/journal.pone.0088334] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 01/06/2014] [Indexed: 01/09/2023] Open
Abstract
Objective To examine single nucleotide polymorphism (SNPs) in MUC16 (CA125) and MUC1 (CA15.3) in relation to ovarian cancer risk and survival. Methods We genotyped germline variants of MUC16 (rs2547065, rs1559168, rs12984471, rs2121133) and MUC1 (rs2070803, rs4072037, rs1045253) using samples collected from 758 ovarian cancer cases and 788 controls enrolled in the New England Case-Control Study between 2003 and 2008. We calculated age-adjusted odds ratios (OR) and 95% confidence intervals (CIs) for disease risk using unconditional and polytomous logistic regression and hazard ratios (HR) for survival using Cox proportional hazard ratios. In a subset of cases, we compared log-normalized CA125 values by genotype using generalized linear models. Results Cases homozygous for the variant allele of MUC16 SNP, rs12984471, had poorer overall survival (log-rank p = 0.03) and higher CA125 levels, especially cases over age 65 (p = 0.01). For MUC1 SNP, rs4072037, women homozygous for the G variant had a non-significantly decreased risk for serous invasive types but elevated risk for serous borderline tumors, mucinous borderline and invasive tumors, and endometrioid tumors. Women with the variant allele of MUC16 SNP, rs2547065, especially those who were homozygous had an elevated risk for ovarian cancer; but this association was not confirmed in an independent dataset. Conclusion This targeted screen of seven polymorphisms of MUC16 and MUC1 genes failed to identify and confirm effects on ovarian cancer risk overall. However, there may be effects of MUC16 rs12984471 on survival and MUC1 rs4072037 on risk for histologic types of ovarian cancer other than invasive serous. Further study is warranted.
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MESH Headings
- Adenocarcinoma, Mucinous/genetics
- Adenocarcinoma, Mucinous/mortality
- Adenocarcinoma, Mucinous/pathology
- Age Factors
- Aged
- CA-125 Antigen/genetics
- Carcinoma, Endometrioid/genetics
- Carcinoma, Endometrioid/mortality
- Carcinoma, Endometrioid/pathology
- Case-Control Studies
- Cystadenoma, Serous/genetics
- Cystadenoma, Serous/mortality
- Cystadenoma, Serous/pathology
- Female
- Homozygote
- Humans
- Membrane Proteins/genetics
- Middle Aged
- Mucin-1/genetics
- Ovarian Neoplasms/genetics
- Ovarian Neoplasms/mortality
- Ovarian Neoplasms/pathology
- Polymorphism, Single Nucleotide
- Proportional Hazards Models
- Risk Factors
- Survival Analysis
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Affiliation(s)
- Kristina A. Williams
- Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Kathryn L. Terry
- Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
| | - Shelley S. Tworoger
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Allison F. Vitonis
- Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
| | - Linda J. Titus
- Department of Community & Family Medicine, Department of Pediatrics, Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire, United States of America
| | - Daniel W. Cramer
- Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
- * E-mail:
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He C, Chen M, Liu J, Yuan Y. Host genetic factors respond to pathogenic step-specific virulence factors of Helicobacter pylori in gastric carcinogenesis. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2014; 759:14-26. [PMID: 24076409 DOI: 10.1016/j.mrrev.2013.09.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/13/2013] [Accepted: 09/13/2013] [Indexed: 12/18/2022]
Abstract
The interindividual differences in risk of Helicobacter pylori (H. pylori)-associated gastric cancer involve significant heterogeneities of both host genetics and H. pylori strains. Several recent studies proposed a distinct sequence for H. pylori exerting its virulence in the host stomach: (i) adhering to and colonizing the surface of gastric epithelial cells, (ii) evading and attenuating the host defense, and (iii) invading and damaging the gastric mucosa. This review focuses on several key issues that still need to be clarified, such as which virulence factors of H. pylori are involved in the three pathogenic steps, which host genes respond to the step-specific virulence factors, and whether and/or how the corresponding host genetic variations influence the risk of gastric carcinogenesis. Urease, BabA and SabA in the adhesion-step, PGN and LPS in the immune evasion-step, and CagA, VacA and Tipα in the mucosal damage-step were documented to play an important role in step-specific pathogenicity of H. pylori infection. There is evidence further supporting a role of potentially functional polymorphisms of host genes directly responding to these pathogenic step-specific virulence factors in the susceptibility of gastric carcinogenesis, especially for urease-interacting HLA class II genes, BabA-interacting MUC1, PGN-interacting NOD1, LPS-interacting TLR4, and CagA-interacting PTPN11 and CDH1. With the continuous improvement of understanding the genetic profile of H. pylori-associated gastric carcinogenesis, a person at increased risk for gastric cancer may benefit from several aspects of efforts: (i) prevent H. pylori infection with a vaccine targeting certain step-specific virulence factor; (ii) eradicate H. pylori infection by blocking step-specific psychopathological characteristics of virulence factors; and (iii) adjust host physiological function to resist the carcinogenic role of step-specific virulence factors or interrupt the cellular signal transduction of the interplay between H. pylori and host in each pathogenic step, especially for the subjects with precancerous lesions in the stomach.
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Affiliation(s)
- Caiyun He
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Moye Chen
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Jingwei Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China.
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Common genetic variants at 1q22 and 10q23 and gastric cancer susceptibility in a Korean population. Tumour Biol 2013; 35:3133-7. [PMID: 24254309 DOI: 10.1007/s13277-013-1409-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 11/08/2013] [Indexed: 02/07/2023] Open
Abstract
Genetic variants at 1q22 and 10q23 were identified as genetic markers of both gastric cancer and esophageal squamous cell carcinoma susceptibility by two genome-wide association studies. The aim of this study was to determine whether rs4072037A > G in MUC1 at 1q22 and rs2274223A > G in PLCE1 at 10q23 are associated with a risk of gastric cancer in a Korean population. We conducted a large-scale case-control study of 3,245 patients with gastric cancer and 1,700 controls. The allele frequencies of rs4072037G and rs2274223G were 11.2 and 25.5% among patients with gastric cancer, compared with 12.8 and 26.4%, respectively, among controls. We found that the rs4072037 AG genotype was significantly associated with a reduced risk of gastric cancer [odds ratios (OR) = 0.78; 95% confidence interval (CI) = 0.67-0.91 for AG vs AA]. Compared with the rs2274223 AA genotype, we found a significant association between the rs2274223 AG genotype and a weakly reduced risk of gastric cancer (OR = 0.87; 95% CI = 0.76-0.99 for AG vs AA). Our data suggest that genetic variants at 1q22 and 10q23 play a role in gastric carcinogenesis.
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Eswaran J, Horvath A, Godbole S, Reddy SD, Mudvari P, Ohshiro K, Cyanam D, Nair S, Fuqua SAW, Polyak K, Florea LD, Kumar R. RNA sequencing of cancer reveals novel splicing alterations. Sci Rep 2013; 3:1689. [PMID: 23604310 PMCID: PMC3631769 DOI: 10.1038/srep01689] [Citation(s) in RCA: 134] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Accepted: 03/01/2013] [Indexed: 12/30/2022] Open
Abstract
Breast cancer transcriptome acquires a myriad of regulation changes, and splicing is critical for the cell to “tailor-make” specific functional transcripts. We systematically revealed splicing signatures of the three most common types of breast tumors using RNA sequencing: TNBC, non-TNBC and HER2-positive breast cancer. We discovered subtype specific differentially spliced genes and splice isoforms not previously recognized in human transcriptome. Further, we showed that exon skip and intron retention are predominant splice events in breast cancer. In addition, we found that differential expression of primary transcripts and promoter switching are significantly deregulated in breast cancer compared to normal breast. We validated the presence of novel hybrid isoforms of critical molecules like CDK4, LARP1, ADD3, and PHLPP2. Our study provides the first comprehensive portrait of transcriptional and splicing signatures specific to breast cancer sub-types, as well as previously unknown transcripts that prompt the need for complete annotation of tissue and disease specific transcriptome.
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Affiliation(s)
- Jeyanthy Eswaran
- McCormick Genomic and Proteomics Center, The George Washington University, Washington, District of Columbia 20037, USA
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Functional polymorphism rs4072037 in MUC1 gene contributes to the susceptibility to gastric cancer: evidence from pooled 6,580 cases and 10,324 controls. Mol Biol Rep 2013; 40:5791-6. [PMID: 24072653 DOI: 10.1007/s11033-013-2682-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Accepted: 09/14/2013] [Indexed: 12/14/2022]
Abstract
Genome-wide association studies have reported a promising association of rs4072037 with gastric cancer (GC). This variant was associated with altered physiological function of MUC1 possibly by modulating promoter activity and alternative splicing of MUC1. However, the association results were inconclusive and estimate of the effect of this variant was not well evaluated. A meta-analysis by systematically reviewing relevant reports may facilitate to address these concerns. Association studies involving MUC1 rs4072037 polymorphism and GC risk were identified up to June 30, 2012. Odds ratio (OR) and 95 % confidence interval (CI) in additive model were estimated or extracted from each study. The pooled effect size was quantitatively synthesized using meta-analysis. Heterogeneity between studies was measured by the Q test and I (2) statistic, and publication bias was evaluated by a funnel plot and the Egger's test. A total of 10 independent case-control studies including 6,580 GC cases and 10,324 controls were included in this meta-analysis. Eight of the ten studies were Asian ethnicity and two European. The G allele of MUC1 rs4072037 was significantly associated with a decreased risk of GC (OR = 0.72, 95 % CI 0.68-0.77; P = 7.82 × 10(-25)), as compared with A allele. Stratification for different ethnicity, tumor localization or type showed similar results. These findings represent important evidence for association of MUC1 rs4072037 variant with GC risk, and also provide a relatively reliable estimate of effect size. MUC1 is a strong candidate as a susceptibility gene of GC.
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Li M, Huang L, Qiu H, Fu Q, Li W, Yu Q, Sun L, Zhang L, Hu G, Hu J, Yuan X. Helicobacter pylori infection synergizes with three inflammation-related genetic variants in the GWASs to increase risk of gastric cancer in a Chinese population. PLoS One 2013; 8:e74976. [PMID: 24069371 PMCID: PMC3777913 DOI: 10.1371/journal.pone.0074976] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Accepted: 08/12/2013] [Indexed: 12/11/2022] Open
Abstract
Background Three recent genome-wide association studies (GWASs) have reported that three SNPs (rs4072037, rs13361707 and rs2274223) located on genes related to host inflammatory response are significantly associated with susceptibility to gastric cancer (GC) in Chinese populations. Helicobacter pylori infection is also an important risk factor for GC through causing inflammatory response in the gastric mucosa. However, no study has established whether there are potential gene-environment interactions between these genetic variants and H. pylori infection to the risk of GC. Methods We genotyped three polymorphisms (rs4072037 at 1q22, rs13361707 at 5p13, and rs2274223 at 10q23) in 335 Chinese gastric adenocarcinoma patients and 334 controls. H. pylori serology was examined by enzyme-linked immunosorbent assay. Multivariable logistic regression models were used to evaluate the association between the variables and GC risk. Results We confirmed that the three SNPs (rs4072037, rs13361707 and rs2274223) were significantly associated with GC susceptibility. H. pylori infection also significantly increased the risk of GC. Furthermore, there were joint effects between H. pylori infection and the three SNPs on the risk of GC. The most elevated risk of GC was found in subjects with H. pylori seropositivity and AA genotypes for rs4072037 [odds ratio (OR), 3.95; 95% confidence interval (CI), 2.29–6.79], H. pylori seropositivity and CT/CC genotypes for rs13361707 (OR, 2.68; 95% CI, 1.62–4.43), H. pylori seropositivity and AG/GG genotypes for rs2274223 (OR, 2.45; 95% CI, 1.55–3.88) compared with those with H. pylori seronegativity and other genotypes of each SNP. Significant interactions were observed between H. pylori seropositivity and the three SNPs (all PG× E <0.05) to the risk of GC. Conclusion These findings indicate that the three SNPs (rs4072037, rs13361707 and rs2274223) identified in the GWASs may interact with H. pylori infection to increase the risk of GC.
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Affiliation(s)
- Miao Li
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Liu Huang
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Qiang Fu
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Wen Li
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Qianqian Yu
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Li Sun
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Lihong Zhang
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Guangyuan Hu
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Junbo Hu
- Department of Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
- * E-mail:
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Yang XX, Li FX, Zhou CP, Hu NY, Wu YS, Li M. Association of genetic polymorphisms at 1q22 but not 10q23 with gastric cancer in a southern Chinese population. Asian Pac J Cancer Prev 2013; 13:2519-22. [PMID: 22938415 DOI: 10.7314/apjcp.2012.13.6.2519] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Data from a recent genome-wide association studiesy of gastric cancer (GC) and oesophageal squamous cell carcinoma in Chinese living in the Taihang Mountains of north-central China suggest that 1q22 and 10q23 are susceptibility-associated regions for GC. However, this has not been confirmed in southern Chinese populations. The aim of this study was to investigate whether these polymorphisms at 1q22 and 10q23 are associated with the risk of GC in a southern Chinese population. METHODS We selected seven top significant associated single nucleotide polymorphisms (SNPs) at 1q22 and 10q23 and conducted a population-based case- control study in a southern Chinese population. Genotypes were determined using MassARRAYTM system (Sequenome, San Diego, CA). RESULTS Two SNPs at 1q22, rs4072037 and rs4460629, were significantly associated with a reduced risk of GC, best fitting the dominant genetic model. Logistic regression models adjusted for age and sex showed that rs4072037 AG and GG (OR=0.64, P=0.017, compared with AA) and rs4460629 CT and TT (OR=0.54, P=0.0016, compared with TT) significantly reduced the risk of GC. However, no significant results for the five SNPs at 10q23 were obtained in this study. CONCLUSION These outcomes indicate that 1q22 is associated with GC susceptibility in this southern Chinese population, while an association for the locus at 10q23 was not confirmed.
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Affiliation(s)
- Xue-Xi Yang
- School of Biotechnology, Southern Medical University, Guangzhou, China
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Saeki N, Ono H, Sakamoto H, Yoshida T. Genetic factors related to gastric cancer susceptibility identified using a genome-wide association study. Cancer Sci 2013; 104:1-8. [PMID: 23057512 PMCID: PMC7657243 DOI: 10.1111/cas.12042] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Revised: 10/03/2012] [Accepted: 10/08/2012] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is one of the major malignant diseases worldwide, especially in Asia, where Japan and Korea have the highest incidence in the world. Gastric cancer is classified into intestinal and diffuse types. While the former is almost absolutely caused by Helicobacter pylori infection as the initial insult, the latter seems to include cases in which the role of infection is limited, if any, and a contribution of genetic factors is anticipated. Previously, we performed a genome-wide association study (GWAS) on diffuse-type GC by using single nucleotide polymorphisms (SNP) catalogued for Japanese population (JSNP), and identified a prostate stem cell antigen (PSCA) gene encoding a glycosylphosphatidylinositol-anchored cell surface antigen as a GC susceptibility gene. From the second candidate locus identified using the GWAS, 1q22, we found the Mucin 1 (MUC1) gene encoding a cell membrane-bound mucin protein as another gene related to diffuse-type GC. A two-allele analysis based on risk genotypes of the two genes revealed approximately 95% of Japanese population have at least one of the two risk genotypes, and approximately 56% of the population have both risk genotypes. The two-SNP genotype might offer ample room to further stratify a high GC risk subpopulation in Japan and Asia by adding another genetic and/or non-genetic factor. Recently, a GWAS on the Chinese population disclosed an additional three GC susceptibility loci: 3q13.31, 5p13.1 and 10q23.
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Affiliation(s)
- Norihisa Saeki
- Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
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Human mucin MUC1 RNA undergoes different types of alternative splicing resulting in multiple isoforms. Cancer Immunol Immunother 2012; 62:423-35. [PMID: 22941036 DOI: 10.1007/s00262-012-1325-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Accepted: 07/20/2012] [Indexed: 10/27/2022]
Abstract
MUC1 is a transmembrane mucin with important functions in normal and transformed cells, carried out by the extracellular domain or the cytoplasmic tail. A characteristic feature of the MUC1 extracellular domain is the variable number of tandem repeats (VNTR) region. Alternative splicing may regulate MUC1 expression and possibly function. We developed an RT-PCR method for efficient isolation of MUC1 mRNA isoforms that allowed us to evaluate the extent of alternative splicing of MUC1 and elucidate some of the rules that govern this process. We cloned and analyzed 21, 24, and 36 isoforms from human tumor cell lines HeLa, MCF7, and Jurkat, respectively, and 16 from normal activated human T cells. Among the 78 MUC1 isoforms we isolated, 76 are new and different cells showed varied MUC1 expression patterns. The VNTR region of exon 2 was recognized as an intron with a fixed 5' splice site but variable 3' splice sites. We also report that the 3506 A/G SNP in exon 2 can regulate 3' splice sites selection in intron 1 and produce different MUC1 short isoform proteins. Furthermore, the SNP A to G mutation was also observed in vivo, during de novo tumor formation in MUC1(+/-)Kras(G12D/+)Pten(loxP/loxP) mice. No specific functions have been associated with previously reported short isoforms. We now report that one new G SNP-associated isoform MUC1/Y-LSP, but not the A SNP-associated isoform MUC1/Y, inhibits tumor growth in immunocompetent but not immunocompromised mice.
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Li FX, Yang XX, He XQ, Hu NY, Wu YS, Li M. Association of 10q23 with colorectal cancer in a Chinese population. Mol Biol Rep 2012; 39:9557-62. [PMID: 22740136 DOI: 10.1007/s11033-012-1820-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Accepted: 06/10/2012] [Indexed: 12/17/2022]
Abstract
Recently, a genome-wide association study of gastric cancer (GC) reported the significant association of seven genetic variants (rs4072037 and rs4460629 on 1q22; rs753724, rs11187842, rs3765524, rs2274223, and rs3781264 on 10q23) with GC in a Chinese population. These findings were confirmed in a subsequent independent study. However, it remains unknown whether these loci are associated with an increased risk of colorectal cancer (CRC). This study was to test whether the seven single nucleotide polymorphisms (SNPs) associated with GC were also associated with CRC in a Chinese population. The seven SNPs were genotyped using MassARRAY system. Allelic, genotypic, and haplotypic associations of the SNPs with CRC were investigated using χ(2) tests and logistic regression analysis. The SNPs rs3765524 and rs2274223, located on 10q23, were found to have significant protective effects against CRC, with equal odds ratios per allele. The two SNPs located on 1q22 (rs4072037 and rs4460629) showed a weak association with CRC. No significant association was identified with CRC for the remaining three SNPs located on 10q23 (rs753724, rs11187842, and rs3781264). These results suggest that rs3765524 and rs2274223 on 10q23 are associated with a protective effect against CRC in a Chinese population.
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Affiliation(s)
- Fen-Xia Li
- School of Biotechnology, Southern Medical University, Guangzhou 510515, China
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Rousseau K, Swallow DM. Mucin methods: genes encoding mucins and their genetic variation with a focus on gel-forming mucins. Methods Mol Biol 2012; 842:1-26. [PMID: 22259127 DOI: 10.1007/978-1-61779-513-8_1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Mucin genes encode the polypeptide backbone of the mucin glycoproteins which are expressed on all epithelial surfaces and are major constituents of the mucus layer. Mucins are, thus, expressed at the interface between the external and the internal environment of the organism, and represent the first line of defence of our body. These genes often have an extensive region of repetitive exonic sequence which codes for the heavily glycosylated domain, whose roles include bacterial interactions and gel hydration. This region shows, in several of the genes, considerable inter-individual variation in repeat number and sequence. Because of their site of expression and their high variability in this important domain, mucin genes are good candidates for conferring differences in genetic susceptibility to multifactorial epithelial and inflammatory disease. However, progress in characterizing the genes has been considerably slower than the rest of the genome because of their size and the GC-rich content of the large, repetitive variable region. Some of the issues relating to the study of these genes are discussed in this chapter. In addition, methods and approaches that have been used successfully are described.
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Affiliation(s)
- Karine Rousseau
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, UK.
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Guo X, Pace RG, Stonebraker JR, Commander CW, Dang AT, Drumm ML, Harris A, Zou F, Swallow DM, Wright FA, O'Neal WK, Knowles MR. Mucin variable number tandem repeat polymorphisms and severity of cystic fibrosis lung disease: significant association with MUC5AC. PLoS One 2011; 6:e25452. [PMID: 21998660 PMCID: PMC3188583 DOI: 10.1371/journal.pone.0025452] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2011] [Accepted: 09/05/2011] [Indexed: 01/20/2023] Open
Abstract
Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for MUC1, MUC2, MUC5AC, and MUC7. VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for MUC1, MUC2, or MUC7. A significant association was found between the overall distribution of MUC5AC VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb HinfI VNTR fragment with severity of lung disease (p = 6.2×10−4 after Bonferroni correction). There was strong LD between MUC5AC VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of MUC5AC was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the MUC5AC 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation.
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Affiliation(s)
- XueLiang Guo
- Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Rhonda G. Pace
- Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Jaclyn R. Stonebraker
- Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Clayton W. Commander
- Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Anthony T. Dang
- Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Mitchell L. Drumm
- Departments of Pediatrics and Genetics, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Ann Harris
- Human Molecular Genetics Program, Children's Memorial Research Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Fei Zou
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Dallas M. Swallow
- Research Department of Genetics, Evolution and Environment, University College London, London, United Kingdom
| | - Fred A. Wright
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Wanda K. O'Neal
- Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Michael R. Knowles
- Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Gene Modifier Study Group, Chapel Hill, North Carolina, United States of America
- * E-mail:
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Zhang H, Jin G, Li H, Ren C, Ding Y, Zhang Q, Deng B, Wang J, Hu Z, Xu Y, Shen H. Genetic variants at 1q22 and 10q23 reproducibly associated with gastric cancer susceptibility in a Chinese population. Carcinogenesis 2011; 32:848-852. [PMID: 21427165 PMCID: PMC3314279 DOI: 10.1093/carcin/bgr051] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2010] [Revised: 02/27/2011] [Accepted: 03/10/2011] [Indexed: 02/05/2023] Open
Abstract
Two recent genome-wide association studies reported significant associations of genetic variants at 1q22, 10q23 and 20p13 with gastric cancer (GC) risk in Chinese populations. However, these findings have not been confirmed in other independent studies. Here, we performed an independent case-control study in a Chinese population by genotyping three loci (rs4072037A>G at 1q22, rs2274223A>G at 10q23 and rs13042395C>T at 20p13) in 1681 GC cases and 1858 controls. We found that rs4072037 at 1q22 and rs2274223 at 10q23 were significantly associated with risk of GC with per allele odds ratio (OR) of 0.72 [95% confidence interval (CI): 0.63-0.81; P = 2.98 × 10(-7)] and 1.42 (95% CI: 1.27-1.58; P = 9.68 × 10(-10)), respectively. The association was more prominent for rs2274223 in female (OR = 1.86, 95% CI: 1.49-2.32) and gastric cardia adenocarcinoma (GCA) (OR = 1.71, 95% CI: 1.49-1.95). Furthermore, we combined the two single-nucleotide polymorphisms to evaluate the joint effect and found that the GC risk significantly increased with the number of risk allele increasing with a trend P value of 6.66 × 10(-16), and individuals with four risk alleles had a 3.28-fold (95% CI: 1.75-6.13) risk of GC compared with those having no risk alleles. However, no significant association was detected between rs13042395 at 20p13 and GC risk (OR = 1.04, 95% CI: 0.94-1.15; P = 0.452). In conclusion, our results indicate that genetic variants at 1q22 and 10q23 but not 20p13 may serve as candidate markers for GC susceptibility in the Chinese population.
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Affiliation(s)
- Hanze Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing 210029, China
| | - Guangfu Jin
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing 210029, China
| | - Huizhang Li
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China
| | - Chuanli Ren
- Medical Lab, Northern Jiangsu People's Hospital, Yangzhou 225001, China
| | - Yanbing Ding
- Department of Gastroenterology, Yangzhou First People's Hospital, Yangzhou 225009, China
| | - Qin Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China
| | - Bin Deng
- Department of Gastroenterology, Yangzhou First People's Hospital, Yangzhou 225009, China
| | - Jianming Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing 210029, China
| | - Yaochu Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China
| | - Hongbing Shen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China
- Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing 210029, China
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Frank B, Weck MN, Müller H, Klopp N, Illig T, Raum E, Brenner H. Polymorphisms in MUC1, MUC2, MUC5B and MUC6 genes are not associated with the risk of chronic atrophic gastritis. Eur J Cancer 2011; 48:114-20. [PMID: 21596555 DOI: 10.1016/j.ejca.2011.04.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Revised: 04/06/2011] [Accepted: 04/11/2011] [Indexed: 12/23/2022]
Abstract
Mucins represent major components of the mucous layer in the stomach, protecting the underlying epithelium from acid, mechanical trauma, proteases and pathogenic bacteria. Previous studies have shown an association of neoplastic transformation in the stomach with aberrant mucin levels, suggesting a potential role of genetic variation in mucin genes in the development of gastric cancer (GC). We assessed the association of genetic variation in candidate single nucleotide polymorphisms (SNPs) in mucin genes with the risk of chronic atrophic gastritis (CAG), a well-established precursor of GC in the German population-based ESTHER study. We genotyped MUC1 T31T, MUC2 L58P, MUC2 V116M, MUC5B E34G, MUC5B R51W, MUC5B rs2014486 (intronic) and MUC6 V619M for 533 serologically defined CAG cases and 1054 age- and sex-matched controls. None of the analysed SNPs was associated with CAG. However, large studies are needed to disclose or exclude potential weak associations of these SNPs with CAG risk.
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Affiliation(s)
- Bernd Frank
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
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Saeki N, Saito A, Choi IJ, Matsuo K, Ohnami S, Totsuka H, Chiku S, Kuchiba A, Lee YS, Yoon KA, Kook MC, Park SR, Kim YW, Tanaka H, Tajima K, Hirose H, Tanioka F, Matsuno Y, Sugimura H, Kato S, Nakamura T, Nishina T, Yasui W, Aoyagi K, Sasaki H, Yanagihara K, Katai H, Shimoda T, Yoshida T, Nakamura Y, Hirohashi S, Sakamoto H. A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer. Gastroenterology 2011; 140:892-902. [PMID: 21070779 DOI: 10.1053/j.gastro.2010.10.058] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2010] [Revised: 10/01/2010] [Accepted: 10/26/2010] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated. METHODS We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants. RESULTS A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10(-13); odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10(-11); OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38). CONCLUSIONS MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.
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Affiliation(s)
- Norihisa Saeki
- Genetics Division, National Cancer Center Research Institute, Tokyo, Japan
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Loh AX, Johnson L, Ng W, Swallow DM. Cis-acting Allelic Variation in MUC5B mRNA Expression is Associated with Different Promoter Haplotypes. Ann Hum Genet 2010; 74:498-505. [DOI: 10.1111/j.1469-1809.2010.00613.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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A comprehensive analysis of common genetic variation in MUC1, MUC5AC, MUC6 genes and risk of stomach cancer. Cancer Causes Control 2010; 21:313-21. [PMID: 19924550 DOI: 10.1007/s10552-009-9463-3] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2009] [Accepted: 10/29/2009] [Indexed: 12/22/2022]
Abstract
OBJECTIVE MUC1, MUC5AC, and MUC6 are main constituents of the mucus barrier in the stomach, which protects the underlying epithelium from acid, proteases, mechanical trauma, and pathogenic microorganisms. Accumulating evidence implicates potential roles of MUC1, MUC5AC, and MUC6 genetic variation in the development of stomach cancer. METHODS We evaluated the relationship between common genetic variations in these genes and stomach cancer risk, using an LD-based tagSNP approach in a population-based case-control study conducted in Warsaw, Poland, during 1994-1996. We genotyped 6, 8, and 14 tagSNPs in MUC1, MUC5AC, and MUC6 genes, respectively, among 273 cases newly diagnosed with stomach cancer and 377 controls. RESULTS Each of the six tagSNPs tested across the MUC1 region showed statistically significant associations with an increased risk of stomach cancer. Carriers of the haplotype ACTAA rare alleles of rs4971052, rs4276913, rs4971088, rs4971092, and rs4072037 had a nearly doubled risk (OR = 1.93, 95% CI = 1.49-2.48) compared to the referent haplotype GTAAG. Out of the eight tagSNPs across MUC5AC region, only minor allele of rs868903 was significantly associated with an increased risk of stomach cancer (OR = 1.80, 95% CI = 1.22-2.63). CONCLUSIONS Overall, our data provide evidence that some common variations in MUC1 and MUC5AC genes contribute to an elevated risk of stomach cancer. Further studies are needed to confirm these novel findings.
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Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37:e67. [PMID: 19339519 PMCID: PMC2685110 DOI: 10.1093/nar/gkp215] [Citation(s) in RCA: 2047] [Impact Index Per Article: 127.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Thousands of mutations are identified yearly. Although many directly affect protein expression, an increasing proportion of mutations is now believed to influence mRNA splicing. They mostly affect existing splice sites, but synonymous, non-synonymous or nonsense mutations can also create or disrupt splice sites or auxiliary cis-splicing sequences. To facilitate the analysis of the different mutations, we designed Human Splicing Finder (HSF), a tool to predict the effects of mutations on splicing signals or to identify splicing motifs in any human sequence. It contains all available matrices for auxiliary sequence prediction as well as new ones for binding sites of the 9G8 and Tra2-β Serine-Arginine proteins and the hnRNP A1 ribonucleoprotein. We also developed new Position Weight Matrices to assess the strength of 5′ and 3′ splice sites and branch points. We evaluated HSF efficiency using a set of 83 intronic and 35 exonic mutations known to result in splicing defects. We showed that the mutation effect was correctly predicted in almost all cases. HSF could thus represent a valuable resource for research, diagnostic and therapeutic (e.g. therapeutic exon skipping) purposes as well as for global studies, such as the GEN2PHEN European Project or the Human Variome Project.
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