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Yu J, Wang CG. Relationship between polymorphisms in homologous recombination repair genes RAD51 G172T、XRCC2 & XRCC3 and risk of breast cancer: A meta-analysis. Front Oncol 2023; 13:1047336. [PMID: 36761956 PMCID: PMC9903134 DOI: 10.3389/fonc.2023.1047336] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 01/09/2023] [Indexed: 01/26/2023] Open
Abstract
Background Genetic variability in DNA double-strand break repair genes such as RAD51 gene and its paralogs XRCC2、XRCC3 may contribute to the occurrence and progression of breast cancer. To obtain a complete evaluation of the above association, we performed a meta-analysis of published studies. Methods Electronic databases, including PubMed, EMBASE, Web of Science, and Cochrane Library, were comprehensively searched from inception to September 2022. The Newcastle-Ottawa Scale (NOS) checklist was used to assess all included non-randomized studies. Odds ratios (OR) with 95% confidence intervals (CI) were calculated by STATA 16.0 to assess the strength of the association between single nucleotide polymorphisms (SNPs) in these genes and breast cancer risk. Subsequently, the heterogeneity between studies, sensitivity, and publication bias were performed. We downloaded data from The Cancer Genome Atlas (TCGA) and used univariate and multivariate Cox proportional hazard regression (CPH) models to validate the prognostic value of these related genes in the R software. Results The combined results showed that there was a significant correlation between the G172T polymorphism and the susceptibility to breast cancer in the homozygote model (OR= 1.841, 95% CI=1.06-3.21, P=0.03). Furthermore, ethnic analysis showed that SNP was associated with the risk of breast cancer in Arab populations in homozygous models (OR=3.52, 95% CI=1.13-11.0, P= 0.003). For the XRCC2 R188H polymorphism, no significant association was observed. Regarding polymorphism in XRCC3 T241M, a significantly increased cancer risk was only observed in the allelic genetic model (OR=1.05, 95% CI= 1.00-1.11, P=0.04). Conclusions In conclusion, this meta-analysis suggests that Rad51 G172T polymorphism is likely associated with an increased risk of breast cancer, significantly in the Arab population. The relationship between the XRCC2 R188H polymorphism and breast cancer was not obvious. And T241M in XRCC3 may be associated with breast cancer risk, especially in the Asian population.
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Crespo-Orta I, Ortiz C, Encarnación J, Suárez E, Matta J. Association between DNA repair capacity and body mass index in women. Mutat Res 2023; 826:111813. [PMID: 36621052 PMCID: PMC10200731 DOI: 10.1016/j.mrfmmm.2022.111813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 12/23/2022] [Accepted: 12/30/2022] [Indexed: 01/02/2023]
Abstract
OBJECTIVE Examine whether DNA repair capacity (DRC) levels are associated with body mass index (BMI) in adult women. DESIGN AND PARTICIPANTS A nested study composed of 539 women without breast cancer (BC) from a case-control BC study in addition to 104 that were recruited later for a total of 643. MEASUREMENTS DRC levels were measured in lymphocytes using a host-cell reactivation assay with a luciferase reporter gene damaged by UVC. This assay measures the efficiency of nucleotide excision repair (NER). Log-binomial regression model was used. The prevalence ratio (PR) was used to evaluate the magnitude of the association between the BMI and DRC levels. An assessment of interaction terms was performed with the likelihood ratio test. The confounding effect was assessed by comparing the point estimates of the crude and adjusted PR. RESULTS The 75th percentiles of DRC levels of the women with a BMI between 18 and 25 and > 25 showed statistically significant differences. The prevalence of a DRC ≤ 5 % among women with BMI > 25 is 1.24 (95 % CI: 1.03, 1.48) times the prevalence of having a DRC ≤ 5 % among the women with BMI ≤ 25 after adjustments for different covariates. This excess was statistically significant (p < 0.05). Women with a family history of cancer had an estimated PR of 1.25 (95 % CI, 0.87-1.39; P ≥ 0.05); and women with no family history of cancer, the estimated PR was 1.6 (95 % CI, 1.14-2.22; p ≤ 0.05). CONCLUSIONS Women with BMI > 25 tend to have lower DRC levels. When having a family history of cancer, the PR of low DRC levels in overweight/obese individuals was not statistically significant. However, the PR of low levels of DRC in overweight/obese individuals with no family history of cancer was statistically significant.
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Affiliation(s)
- Ian Crespo-Orta
- Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University-School of Medicine, Ponce, Puerto Rico.
| | - Carmen Ortiz
- Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University-School of Medicine, Ponce, Puerto Rico
| | - Jarline Encarnación
- Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University-School of Medicine, Ponce, Puerto Rico
| | - Erick Suárez
- Department of Biostatistics and Epidemiology, Graduate School of Public Health, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico
| | - Jaime Matta
- Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University-School of Medicine, Ponce, Puerto Rico.
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Wu HC, Kehm R, Santella RM, Brenner DJ, Terry MB. DNA repair phenotype and cancer risk: a systematic review and meta-analysis of 55 case-control studies. Sci Rep 2022; 12:3405. [PMID: 35233009 PMCID: PMC8888613 DOI: 10.1038/s41598-022-07256-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 02/15/2022] [Indexed: 01/01/2023] Open
Abstract
DNA repair phenotype can be measured in blood and may be a potential biomarker of cancer risk. We conducted a systematic review and meta-analysis of epidemiological studies of DNA repair phenotype and cancer through March 2021. We used random-effects models to calculate pooled odds ratios (ORs) of cancer risk for those with the lowest DNA repair capacity compared with those with the highest capacity. We included 55 case–control studies that evaluated 12 different cancers using 10 different DNA repair assays. The pooled OR of cancer risk (all cancer types combined) was 2.92 (95% Confidence Interval (CI) 2.49, 3.43) for the lowest DNA repair. Lower DNA repair was associated with all studied cancer types, and pooled ORs (95% CI) ranged from 2.02 (1.43, 2.85) for skin cancer to 7.60 (3.26, 17.72) for liver cancer. All assays, except the homologous recombination repair assay, showed statistically significant associations with cancer. The effect size ranged from 1.90 (1.00, 3.60) for the etoposide-induced double-strand break assay to 5.06 (3.67, 6.99) for the γ-H2AX assay. The consistency and strength of the associations support the use of these phenotypic biomarkers; however large-scale prospective studies will be important for understanding their use related to age and screening initiation.
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Affiliation(s)
- Hui-Chen Wu
- Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, 630 West 168th St., Room P&S 16-421E, New York, NY, 10032, USA. .,Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
| | - Rebecca Kehm
- Department of Epidemiology, Mailman School of Public Health of Columbia University, New York, NY, USA
| | - Regina M Santella
- Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, 630 West 168th St., Room P&S 16-421E, New York, NY, 10032, USA.,Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA
| | - David J Brenner
- Center for Radiological Research, Columbia University Irving Medical Center, 630W 168th Street, New York, NY, 10032, USA
| | - Mary Beth Terry
- Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, 630 West 168th St., Room P&S 16-421E, New York, NY, 10032, USA.,Department of Epidemiology, Mailman School of Public Health of Columbia University, New York, NY, USA
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4
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Atkin ND, Raimer HM, Wang Z, Zang C, Wang YH. Assessing acute myeloid leukemia susceptibility in rearrangement-driven patients by DNA breakage at topoisomerase II and CCCTC-binding factor/cohesin binding sites. Genes Chromosomes Cancer 2021; 60:808-821. [PMID: 34405474 PMCID: PMC8511143 DOI: 10.1002/gcc.22993] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 08/12/2021] [Accepted: 08/14/2021] [Indexed: 12/29/2022] Open
Abstract
An initiating DNA double strand break (DSB) event precedes the formation of cancer-driven chromosomal abnormalities, such as gene rearrangements. Therefore, measuring DNA breaks at rearrangement-participating regions can provide a unique tool to identify and characterize susceptible individuals. Here, we developed a highly sensitive and low-input DNA break mapping method, the first of its kind for patient samples. We then measured genome-wide DNA breakage in normal cells of acute myeloid leukemia (AML) patients with KMT2A (previously MLL) rearrangements, compared to that of nonfusion AML individuals, as a means to evaluate individual susceptibility to gene rearrangements. DNA breakage at the KMT2A gene region was significantly greater in fusion-driven remission individuals, as compared to nonfusion individuals. Moreover, we identified select topoisomerase II (TOP2)-sensitive and CCCTC-binding factor (CTCF)/cohesin-binding sites with preferential DNA breakage in fusion-driven patients. Importantly, measuring DSBs at these sites, in addition to the KMT2A gene region, provided greater predictive power when assessing individual break susceptibility. We also demonstrated that low-dose etoposide exposure further elevated DNA breakage at these regions in fusion-driven AML patients, but not in nonfusion patients, indicating that these sites are preferentially sensitive to TOP2 activity in fusion-driven AML patients. These results support that mapping of DSBs in patients enables discovery of novel break-prone regions and monitoring of individuals susceptible to chromosomal abnormalities, and thus cancer. This will build the foundation for early detection of cancer-susceptible individuals, as well as those preferentially susceptible to therapy-related malignancies caused by treatment with TOP2 poisons.
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MESH Headings
- Binding Sites/genetics
- CCCTC-Binding Factor/blood
- CCCTC-Binding Factor/genetics
- Cell Cycle Proteins/blood
- Cell Cycle Proteins/genetics
- Chondroitin Sulfate Proteoglycans/blood
- Chondroitin Sulfate Proteoglycans/genetics
- Chromosomal Proteins, Non-Histone/blood
- Chromosomal Proteins, Non-Histone/genetics
- Chromosome Aberrations
- DNA Breaks, Double-Stranded/drug effects
- DNA Repair/genetics
- DNA Topoisomerases, Type II/blood
- DNA Topoisomerases, Type II/genetics
- DNA-Binding Proteins/blood
- DNA-Binding Proteins/genetics
- Etoposide/pharmacology
- Female
- Gene Rearrangement/genetics
- Genome, Human/genetics
- HeLa Cells
- Histone-Lysine N-Methyltransferase/blood
- Histone-Lysine N-Methyltransferase/genetics
- Humans
- Leukemia, Myeloid, Acute/blood
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/pathology
- Male
- Myeloid-Lymphoid Leukemia Protein/blood
- Myeloid-Lymphoid Leukemia Protein/genetics
- Oncogene Proteins, Fusion/genetics
- Poly-ADP-Ribose Binding Proteins/blood
- Poly-ADP-Ribose Binding Proteins/genetics
- Cohesins
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Affiliation(s)
- Naomi D. Atkin
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, 22908-0733, USA
| | - Heather M. Raimer
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, 22908-0733, USA
| | - Zhenjia Wang
- Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, 22908-0733, USA
| | - Chongzhi Zang
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, 22908-0733, USA
- Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, 22908-0733, USA
- Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, 22908-0733, USA
| | - Yuh-Hwa Wang
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, 22908-0733, USA
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Zhou S, Zhu Q, Liu H, Jiang S, Zhang X, Peng C, Yang G, Li J, Cheng L, Zhong R, Zeng Q, Miao X, Lu Q. Associations of polycyclic aromatic hydrocarbons exposure and its interaction with XRCC1 genetic polymorphism with lung cancer: A case-control study. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 290:118077. [PMID: 34523522 DOI: 10.1016/j.envpol.2021.118077] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 08/27/2021] [Accepted: 08/29/2021] [Indexed: 06/13/2023]
Abstract
Humans are extensively exposed to polycyclic aromatic hydrocarbons (PAHs) daily via multiple pathways. Epidemiological studies have demonstrated that occupational exposure to PAHs increases the risk of lung cancer, but related studies in the general population are limited. Hence, we conducted a case-control study among the Chinese general population to investigate the associations between PAHs exposure and lung cancer risk and analyze the modifications of genetic polymorphisms in DNA repair genes. In this study, we enrolled 122 lung cancer cases and 244 healthy controls in Wuhan, China. Urinary PAHs metabolites were determined by gas chromatography-mass spectrometry, and rs25487 in X-ray repair cross-complementation 1 (XRCC1) gene was genotyped by the Agena Bioscience MassARRAY System. Then, multivariable logistic regression models were performed to estimate the potential associations. We found that urinary hydroxynaphthalene (OH-Nap), hydroxyphenanthrene (OH-Phe) and the sum of hydroxy PAHs (∑OH-PAHs) levels were significantly higher in lung cancer cases than those in controls. After adjusting for gender, age, BMI, smoking status, smoking pack-years, drinking status and family history, urinary ∑OH-Nap and ∑OH-Phe levels were positively associated with lung cancer risk, with dose-response relationships. Compared with those in the lowest tertiles, individuals in the highest tertiles of ∑OH-Nap and ∑OH-Phe had a 2.13-fold (95% CI: 1.10, 4.09) and 2.45-fold (95% CI: 1.23, 4.87) increased risk of lung cancer, respectively. Effects of gender, age, smoking status and smoking pack-years on the associations of PAHs exposure with lung cancer risk were shown in the subgroup analysis. Furthermore, associations of urinary ∑OH-Nap and ∑OH-PAHs levels with lung cancer risk were modified by XRCC1 rs25487 (Pinteraction ≤ 0.025), and were more pronounced in wild-types of rs25487. These findings suggest that environmental exposure to naphthalene and phenanthrene is associated with increased lung cancer risk, and polymorphism of XRCC1 rs25487 might modify the naphthalene exposure-related lung cancer effect.
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Affiliation(s)
- Shuang Zhou
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Qiuqi Zhu
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Huimin Liu
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Shunli Jiang
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China; Key Laboratory of Occupational Health and Environmental Medicine, Department of Public Health, Jining Medical University, 133 Hehua Road, Jining, Shandong, 272067, China
| | - Xu Zhang
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Cheng Peng
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Guanlin Yang
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Jiaoyuan Li
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, Hubei, 430030, China
| | - Liming Cheng
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, Hubei, 430030, China
| | - Rong Zhong
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Qiang Zeng
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Xiaoping Miao
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Qing Lu
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China.
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6
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Abdalhabib EK, Jackson DE, Alzahrani B, Elfaki E, Hamza A, Mohamed Elasbali A, Alanazi F, Algarni A, Khider Ibrahim I, Saboor M. Age- and Gender-Independent Association of XRCC1 Arg399Gln Polymorphism with Chronic Myeloid Leukemia. Int J Gen Med 2021; 14:8231-8236. [PMID: 34815696 PMCID: PMC8605866 DOI: 10.2147/ijgm.s340283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/04/2021] [Indexed: 11/23/2022] Open
Abstract
Purpose DNA damage to hematopoietic progenitor cells is an essential factor for leukemia development as a failure of the host DNA repair system to fix errors in DNA. This study aimed to assess the association of XRCC1 gene polymorphisms including Arg194Trp, Arg399Gln, and Arg280His with the risk of development of CML in Sudanese population. Patients and Methods The present study was conducted on 186 newly diagnosed patients with CML, aged 19–70 years (118 males and 68 females; mean age of 46.15±13.91 years) and 186 normal healthy controls (123 males and 63 females; mean age of 44.94±8.97 years). Polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay was utilized to analyze the XRCC1 (Arg194Trp, Arg399Gln, and Arg280His) gene polymorphisms. Results The genotypic frequencies of Arg399Gln polymorphism in cases were 131 (70.4%) homozygous Arg/Arg, 46 (24.7%) homozygous Gln/Gln, and 9 (4.8%) heterozygous Arg/Gln as compared to the controls ie, 153 (82.3%), 73 (14.5%), and 6 (3.2%), respectively. The Arg399Gln variant genotypic frequencies significantly differed between the cases and controls (χ2 = 7.249, P = 0.027). By comparison, no statistically significant difference was observed in the variant genotype frequencies between the cases and controls in terms of Arg194Trp and Arg280His polymorphisms. Conclusion XRCC1 Arg399Gln gene polymorphism might have an important role in increasing the risk of chronic myeloid leukemia among Sudanese patients. Furthermore, all tested three polymorphisms showed no association of risk of the development of CML with age and gender.
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Affiliation(s)
- Ezeldine K Abdalhabib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, AlQurayyat, Jouf University, Sakaka, Saudi Arabia
| | - Denise E Jackson
- Thrombosis and Vascular Diseases Laboratory, School of Health and Biomedical Sciences, RMIT University, Victoria, Australia
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, AlQurayyat, Jouf University, Sakaka, Saudi Arabia
| | - Elyasa Elfaki
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, AlQurayyat, Jouf University, Sakaka, Saudi Arabia
| | - Alneil Hamza
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, AlQurayyat, Jouf University, Sakaka, Saudi Arabia
| | - Abdelbaset Mohamed Elasbali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, AlQurayyat, Jouf University, Sakaka, Saudi Arabia
| | - Fehaid Alanazi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, AlQurayyat, Jouf University, Sakaka, Saudi Arabia
| | - Abdulrahman Algarni
- Department of Medical Laboratory Technology, College of Applied Medical Sciences, Northern Borders University, Arar, Saudi Arabia
| | - Ibrahim Khider Ibrahim
- Department of Hematology, Faculty of Medical Laboratory Sciences, Al Neelain University, Khartoum, Sudan
| | - Muhammad Saboor
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.,Medical Research Center (MRC), Jazan University, Jazan, Saudi Arabia
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Liu J, Zheng J, Guo Y, Sheng X, Yin Y, Qian S, Xu B, Xiong W, Yin X. Association between APE1 rs1760944 and rs1130409 polymorphism with prostate cancer risk: A systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e27630. [PMID: 34797286 PMCID: PMC8601344 DOI: 10.1097/md.0000000000027630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 10/13/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Recently, some studies have suggested that the association of apurinic/apyrimidinic endonuclease 1 (APE1) gene polymorphism with prostate cancer (PCa) risk, but there are still some controversies. Hence, we elaborated the relationship between APE1 rs1760944 and rs1130409 gene and PCa risk through systematic literature review and meta-analysis. METHODS As of March 2020, EMBASE, PubMed, the Cochrane Library, Science Direct/Elsevier, MEDLINE and CNKI were used for systematic literature retrieval to investigate the correlation between APE1 rs1760944 and rs1130409 gene polymorphism with PCa risk. Meta-analysis was performed using Review Manager and Stata software. RESULTS Seven studies were distinguished, consists of 1769 cases of PCa patients and 2237 normal controls. Our results illustrated that there are significant correlation between the APE1 rs1760944 gene polymorphism and PCa in all genetic models (P < .05). The combined odds ratios and 95% confidence intervals were as follows: Additive model (ORs 0.62, 95%, CI [0.39, 0.97]); Codominant model (ORs 0.74, 95% CI [0.58, 0.95]); Dominant model (ORs 0.75, 95%, CI [0.59, 0.95]); Recessive model (ORs 0.63, 95% CI [0.41, 0.96]); Allele model (ORs 0.78, 95% CI [0.65, 0.94]). There also have significant associations between APE1 rs1130409 polymorphisms and PCa in all genetic models (P < .05). The combined odds ratios and 95% confidence intervals were as follows: Additive model (ORs 1.37, 95%, CI [1.01, 1.85]); Codominant model (ORs 1.21, 95% CI [1.01, 1.44]); Dominant model (ORs 1.33, 95%, CI [1.02, 1.73]); Recessive model (ORs 1.74, 95% CI [1.06, 2.85]); Allele model (ORs 1.14, 95% CI [1.00, 1.29]). CONCLUSION This study suggests that APE1 rs1760944 polymorphisms might be a protective factor of PCa, and APE1 rs1130409 is suggested to be a risk factor of PCa. APE1 rs1760944 and rs1130409 polymorphisms may be used in the risk assessment of PCa.
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Affiliation(s)
- Jinnian Liu
- Department of Urology, Second People's Hospital of Banan District, Chongqing, China
| | - Jian Zheng
- Department of Urology, Second People's Hospital of Banan District, Chongqing, China
| | - Yu Guo
- Department of Urology, Traditional Chinese Medicine Hospital, Chongqing, China
| | - Xia Sheng
- Department of Urology, Second People's Hospital of Banan District, Chongqing, China
| | - Yongjian Yin
- Department of Urology, Second People's Hospital of Banan District, Chongqing, China
| | - Shengqiang Qian
- Department of Urology, Traditional Chinese Medicine Hospital, Chongqing, China
| | - Bin Xu
- Department of Urology, Traditional Chinese Medicine Hospital, Chongqing, China
| | - Wei Xiong
- Department of Urology, Traditional Chinese Medicine Hospital, Chongqing, China
| | - Xiangrui Yin
- Department of Urology, Traditional Chinese Medicine Hospital, Chongqing, China
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8
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Fan Y, Gao Z, Li X, Wei S, Yuan K. Gene expression and prognosis of x-ray repair cross-complementing family members in non-small cell lung cancer. Bioengineered 2021; 12:6210-6228. [PMID: 34486486 PMCID: PMC8806547 DOI: 10.1080/21655979.2021.1964193] [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] [Indexed: 12/24/2022] Open
Abstract
The X-ray repair cross-complementing gene (XRCC) family participates in DNA damage repair and its dysregulation is associated with the development and progression of a variety of cancers. However, XRCCs have not been systematically studied in non-small cell lung cancer (NSCLC). Using The Cancer Genome Atlas (TCGA) and Oncomine databases, we compared the expression levels of XRCCs between NSCLC and normal tissues and performed survival analysis using the data from TCGA. The correlations of XRCCs with the clinical parameters were then analyzed using UCSC Xena. Genetic alterations in XRCCs in NSCLC and their effects on the prognosis of patients were presented using cBioPortal. SurvivalMeth was used to explore the differentially methylated sites associated with NSCLC and their effect on prognosis. Next, the immunological correlations of XRCCs expression level were analyzed using TIMER 2.0. Finally, GeneMANIA was used to visualize and analyze the functionally relevant genes, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for functional and pathway enrichment analyses of prognostic genes. Our results revealed that XRCCs were overexpressed in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Univariate and multivariate Cox analyses showed that XRCC4/5/6 were independent risk factors for LUAD. Additionally, genetic alterations, methylation, and immune cell infiltration demonstrated an association between XRCC4/5/6 and poor prognosis in LUAD. Finally, the KEGG-enriched and non-homologous end-joining (NHEJ) pathways were shown to be associated with XRCC4/5/6. In conclusion, our study demonstrated that XRCC4/5/6 could be used as diagnostic and prognostic biomarkers for LUAD.
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Affiliation(s)
- Yongfei Fan
- Department of Thoracic Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou China
| | - Zhaojia Gao
- Department of Thoracic Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou China.,Heart and Lung Disease Laboratory, the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou China
| | - Xinwei Li
- Department of Gastroenterology, Affiliated Cancer Hospital of Bengbu Medical College, Bengbu China
| | - Shuzhang Wei
- Department of Urology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou China
| | - Kai Yuan
- Department of Thoracic Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou China.,Heart and Lung Disease Laboratory, the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou China
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Shelke S, Das B. Radio-adaptive response and correlation of non-homologous end joining repair gene polymorphisms [XRRC5 (3R/2R/1R/0R), XRCC6(C/G) and XRCC7 (G/T)] in human peripheral blood mononuclear cells exposed to gamma radiation. Genes Environ 2021; 43:9. [PMID: 33685509 PMCID: PMC7938547 DOI: 10.1186/s41021-021-00176-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 02/05/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Radio-adaptive response (RAR) is transient phenomena, where cells conditioned with a small dose (priming) of ionizing radiation shows significantly reduced DNA damage with a subsequent high challenging dose. The role of DNA double strand break repair gene polymorphism in RAR is not known. In the present study attempt was made to find out the influence of NHEJ repair gene polymorphisms [a VNTR; XRCC5 (3R/2R/1R/0R); two single nucleotide polymorphisms (SNPs); XRCC6 (C/G) and XRCC7 (G/T)] with DNA damage, repair and mRNA expression in human PBMCs in dose and adaptive response studies. Genomic DNA extracted from venous blood samples of 20 random healthy donors (16 adaptive and 4 non-adaptive) and genotyping of NHEJ repair genes was carried out using PCR amplified length polymorphism. RESULTS The dose response study revealed significant positive correlation of genotypes at XRRC5 (3R/2R/1R/0R), XRCC6(C/G) and XRCC7 (G/T) with DNA damage. Donors having genotypes with 2R allele at XRCC5 showed significant positive correlation with mRNA expression level (0R/2R: r = 0.846, P = 0.034; 1R/2R: r = 0.698, P = 0.0001 and 2R/2R: r = 0.831, P = 0.0001) for dose response. Genotypes C/C and C/G of XRCC6 showed a significant positive correlation (P = 0.0001), whereas, genotype T/T of XRCC7 showed significant negative correlation (r = - 0.376, P = 0.041) with mRNA expression. CONCLUSION Interestingly, adaptive donors having C/G genotype of XRCC6 showed significantly higher (P < 0.05) mRNA expression level in primed cells suggesting their role in RAR. In addition, NHEJ repair gene polymorphisms play crucial role with radio-sensitivity and RAR in human PBMCs.
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Affiliation(s)
- Shridevi Shelke
- Low Level Radiation Research Section, Radiation Biology & Health Sciences Division, Bio-Sciences Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India
| | - Birajalaxmi Das
- Low Level Radiation Research Section, Radiation Biology & Health Sciences Division, Bio-Sciences Group, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India.
- Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, 400094, India.
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Assessment on the influence of TLR4 and DNA repair genes in laryngeal cancer susceptibility: a selective examination in a Romanian case control study. REV ROMANA MED LAB 2021. [DOI: 10.2478/rrlm-2021-0005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Abstract
Background: Tumor characterization through the study of molecular biology has become an invaluable tool in understanding cancer development and evolution due to its relationship with chromosomal mutations, alterations or aberrations. The purpose of this study was to investigate the involvement of genes such as TLR-4 and DNA repair pathways (XRCC1 and XPD) in laryngeal cancer susceptibility in a Romanian population. Method: We performed a case-control study on 157 laryngeal cancer patients and 101 healthy controls. Genetic testing was carried out using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. Results: We identified the Gln allele of the XPDLys751Gln polymorphism as an individual risk factor in laryngeal cancer development (Gln vs Lys, adjusted OR=1.65, 95%CI=1.13–2.40, P=0.008). Subjects with the mutant homozygote variant (Gln/Gln) had a two fold increase in cancer risk (adjusted OR=2.18, 95%CI=1.06–4.47, p=0.028) when compared to the reference wild type genotype (Lys/Lys). Stratification by sex and age, identified males under 62 years as the most susceptible group with an almost three fold risk (adjusted OR=2.94, 95%CI=1.31–6.59, p=0.007) for the dominant model (Lys/Gln+Gln/Gln). No associations were found for TLR-4Thr399Ile, XRCC1Arg194Trp and XRCC1Arg399Gln. Conclusion: The results of the study show that the XPDLys751Gln polymorphism may be among other independent risk factors for developing laryngeal cancer where as TLR-4Thr399Ile, XRCC1Arg194Trp and XRCC1 Arg399Gln show no such association. However, we consider the relative small number of the subjects selected for this analyses a possible limitation towards the real influence the obtain results may pertain in laryngeal cancer evolution.
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Oshi M, Kim TH, Tokumaru Y, Yan L, Matsuyama R, Endo I, Cherkassky L, Takabe K. Enhanced DNA Repair Pathway is Associated with Cell Proliferation and Worse Survival in Hepatocellular Carcinoma (HCC). Cancers (Basel) 2021; 13:cancers13020323. [PMID: 33477315 PMCID: PMC7830462 DOI: 10.3390/cancers13020323] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary We studied the relationship between enhancement of DNA repair and cancer aggressiveness, tumor immune microenvironment, and patient survival in 749 hepatocellular carcinoma (HCC) patients from 5 cohorts using a DNA repair pathway score. We show that the DNA repair pathway was enhanced by the stepwise carcinogenic process of HCC, notably in grade 3 compared to grade 1 or 2 HCC. DNA repair high HCC was associated with worse survival, elevated intratumor heterogeneity, and mutation load, but not with the fraction of immune cell infiltration nor cytolytic activity. The expression of proliferation- and other cancer aggressiveness-related gene sets was also increased. Interestingly, these features were more pronounced in low-grade compared to high-grade HCC. In conclusion, the DNA repair score may be used to understand the role of DNA repair pathways in patient prognosis and treatment sensitivity and be used to improve patient outcome. To our knowledge, this is the first study using DNA repair pathway-related gene set expression data to examine and validate the clinical relevance of DNA repair pathway activity in HCC. Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies and a leading cause of cancer-related deaths worldwide. In this study, a total of 749 HCC patients from 5 cohorts were studied to examine the relationships between enhancement of DNA repair and cancer aggressiveness, tumor immune microenvironment, and patient survival in HCC, utilizing a DNA repair pathway score. Our findings suggest that the DNA repair pathway was not only enhanced by the stepwise carcinogenic process of HCC, but also significantly enhanced in grade 3 HCC compared with grade 1 and 2 tumors. DNA repair high HCC was associated with worse survival, elevated intratumor heterogeneity, and mutation load, but not with the fraction of immune cell infiltration nor immune response. HCC tumors with a DNA repair high score enriched the cell proliferation- and other cancer aggressiveness-related gene sets. Interestingly, these features were more pronounced in grade 1 and 2 HCC compared to grade 3 HCC. To our knowledge, this is the first study to use DNA repair pathway-related gene set expression data to examine and validate the clinical relevance of DNA repair pathway activity in HCC. The DNA repair score may be used to better understand and predict prognosis in HCC.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (T.H.K.); (Y.T.); (L.C.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Tae Hee Kim
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (T.H.K.); (Y.T.); (L.C.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (T.H.K.); (Y.T.); (L.C.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Leonid Cherkassky
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (T.H.K.); (Y.T.); (L.C.)
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (T.H.K.); (Y.T.); (L.C.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Correspondence: ; Tel.: +1-716-8455540; Fax: +1-716-8451668
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Whitaker AM, Stark WJ, Flynn TS, Freudenthal BD. Molecular and structural characterization of disease-associated APE1 polymorphisms. DNA Repair (Amst) 2020; 91-92:102867. [PMID: 32454397 DOI: 10.1016/j.dnarep.2020.102867] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 12/14/2022]
Abstract
Under conditions of oxidative stress, reactive oxygen species (ROS) continuously assault the structure of DNA resulting in oxidation and fragmentation of the nucleobases. When the nucleobase structure is altered, its base-pairing properties may also be altered, promoting mutations. Consequently, oxidative DNA damage is a major source of the mutation load that gives rise to numerous human maladies, including cancer. Base excision repair (BER) is the primary pathway tasked with removing and replacing mutagenic DNA base damage. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central enzyme with AP-endonuclease and 3' to 5' exonuclease functions during BER, and therefore is key to maintenance of genome stability. Polymorphisms, or SNPs, in the gene encoding APE1 (APEX1) have been identified among specific human populations and result in variants of APE1 with modified function. These defects in APE1 potentially result in impaired DNA repair capabilities and consequently an increased risk of disease for individuals within these populations. In the present study, we determined the X-ray crystal structures of three prevalent disease-associated APE1 SNPs (D148E, L104R, and R237C). Each APE1 SNP results in unique localized changes in protein structure, including protein dynamics and DNA binding contacts. Combined with comprehensive biochemical characterization, including pre-steady-state kinetic and DNA binding analyses, variant APE1:DNA complex structures with both AP-endonuclease and exonuclease substrates were analyzed to elucidate how these SNPs might perturb the two major repair functions employed by APE1 during BER.
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Affiliation(s)
- Amy M Whitaker
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS,66160, USA
| | - Wesley J Stark
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS,66160, USA
| | - Tony S Flynn
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS,66160, USA
| | - Bret D Freudenthal
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS,66160, USA.
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Alanazi JS, Latimer JJ. Host Cell Reactivation: Assay for Actively Transcribed DNA (Nucleotide Excision) Repair Using Luciferase Family Expression Vectors. Methods Mol Biol 2020; 2102:509-528. [PMID: 31989574 DOI: 10.1007/978-1-0716-0223-2_28] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Host cell reactivation (HCR) is a transfection-based assay in which intact cells repair damage localized to exogenous DNA. This chapter provides instructions for the application of this technique, using as an exemplar UV irradiation as a source of damage to a luciferase reporter plasmid. Through measurement of the activity of a successfully transcribed and translated reporter enzyme, the amount of damaged plasmid that a cell can "reactivate" or repair and express can be quantitated. Different DNA repair pathways can be analyzed by this technique by damaging the reporter plasmid in different ways. Since it involves repair of a transcriptionally active gene, when applied to UV damage the HCR assay measures the capacity of the host cells to perform transcription-coupled repair (TCR), a subset of the overall nucleotide excision repair pathway that specifically targets transcribed gene sequences. This method features two ways to perform the assay using expression vectors with luciferase and beta galactosidase, as well as with firefly luciferase and Renilla luciferase using the same luminometer.
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Affiliation(s)
- Jowaher S Alanazi
- Department of Pharmaceutical Sciences, Nova Southeastern University and AutoNation Breast Cancer Institute, Fort Lauderdale, FL, USA
| | - Jean J Latimer
- Department of Pharmaceutical Sciences, Nova Southeastern University and AutoNation Breast Cancer Institute, Fort Lauderdale, FL, USA.
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Dai P, Li J, Li W, Qin X, Wu X, Di W, Zhang Y. Genetic polymorphisms and pancreatic cancer risk: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 2019; 98:e16541. [PMID: 31393355 PMCID: PMC6708677 DOI: 10.1097/md.0000000000016541] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 06/10/2019] [Accepted: 06/27/2019] [Indexed: 01/09/2023] Open
Abstract
BACKGROUNDS Previous investigations yielded inconsistent results for the associations between pancreatic cancer (PC) risk and genetic polymorphisms. The study aimed to perform a systematic review and meta-analysis of studies exploring association of some genetic polymorphisms and PC risk. METHODS We systematically searched on PubMed and Web of Science for association of genetic polymorphisms and PC risk published from 1969 to January 2019. We computed the multivariate odd ratio (OR) and 95% confidence intervals (CI), comparing different genetic types. RESULTS The present meta-analysis showed significant associations between deoxyribonucleic acid (DNA) repair gene (X-ray repair cross-complementing group 1 (XRCC1) Arg399GIn and Arg194Trp, excision repair cross complementation 1 (ERCC1) rs11615 and rs3212986, ERCC2 rs13181) polymorphisms and PC risk. CONCLUSIONS Because of the limited sample size and ethnicity enrolled in the present meta-analysis, further larger scaled studies should be performed to demonstrate the association.
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Affiliation(s)
- Peng Dai
- Department of Hepato-Biliary-Pancreatic Surgery, Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University
| | - Jing Li
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Shanxi Medical University
| | - Weibin Li
- Department of General Surgery, Shanxi Academy of Medical Sciences, Shanxi Dayi Hospital, Taiyuan, Shanxi, China
| | - Xueliang Qin
- Department of Hepato-Biliary-Pancreatic Surgery, Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University
| | - Xiaoyong Wu
- Department of Hepato-Biliary-Pancreatic Surgery, Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University
| | - Weidong Di
- Department of Hepato-Biliary-Pancreatic Surgery, Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University
| | - Yanzhong Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University
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Qiu YL, Xu ZB, Wang Q, Hu JY, Zhang L, Chen SQ, Lyu Y, Wei CL, Yan XY, Wang T. Association between methylation of DNA damage response-related genes and DNA damage in hepatocytes of rats following subchronic exposure to vinyl chloride. CHEMOSPHERE 2019; 227:323-328. [PMID: 30999172 DOI: 10.1016/j.chemosphere.2019.04.058] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 04/08/2019] [Accepted: 04/08/2019] [Indexed: 06/09/2023]
Abstract
In the present study, we investigated the association between methylation of DNA damage response-related genes such as cyclin-dependent kinase inhibitor (CDKN)2A, Ras association (RalGDS/AF-6) domain family member (RASSF)1A, O6-methylguanine DNA methyltransferase (MGMT), Kirsten rat sarcoma viral oncogene homolog (KRAS), and spleen-associated tyrosine kinase (SYK) and DNA damage in hepatocytes of rats following subchronic exposure to vinyl chloride (VC). Sixty-four healthy rats were randomly divided into three VC exposure groups (5, 25, and 125 mg/kg) and an untreated negative control group (n = 16 each). VC was administered by intraperitoneal injection every other day for a total of three times a week. Eight randomly selected rats from each group were sacrificed at the end of 6 and 12 weeks, and liver tissue was harvested for the comet assay and for assessment of DNA methylation level and mRNA expression of related genes by PCR. Overall methylation levels in the genome of hepatocytes in VC-exposed rats were higher than those in the control group at 6 and 12 weeks (P < 0.05), although no differences were observed with regarding to dose (P > 0.05). After 12 weeks of exposure, differences in the methylation of RASSF1A and MGMT promoter regions were observed between the high-dose group and other groups (P < 0.05), whereas no differences were observed for the KRAS, SYK, and CDKN2A promoters (P > 0.05). These results suggest that DNA damage and increased genome-wide methylation are biomarkers for VC exposure and that RASSF1A and MGMT promoter methylation is related to the carcinogenic mechanism of VC.
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Affiliation(s)
- Yu-Lan Qiu
- Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, China.
| | - Zhi-Bin Xu
- Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Qian Wang
- Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Jun-Yang Hu
- Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Lin Zhang
- Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Shi-Qi Chen
- Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Yi Lyu
- Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Cai-Ling Wei
- Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Xiao-Yan Yan
- Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Tong Wang
- Department of Statistics, School of Public Health, Shanxi Medical University, Taiyuan, China
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Lawania S, Singh A, Sharma S, Singh N, Behera D. The multi-faceted high order polymorphic synergistic interactions among nucleotide excision repair genes increase the risk of lung cancer in North Indians. Mutat Res 2019; 816-818:111673. [PMID: 31195348 DOI: 10.1016/j.mrfmmm.2019.111673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 05/08/2019] [Accepted: 06/04/2019] [Indexed: 11/25/2022]
Abstract
It is evident that gene-gene interactions are pervasive in the determination of the susceptibility of human diseases. Polymorphisms in nucleotide excision repair pathway (NER) genes can cause variations in the repair capacity and therefore, might lead to increase in susceptibility towards lung cancer through complex gene-gene and gene-smoking interactions. Logistic regression analysis, along with high order genetic interaction were analyzed using data mining tools such as multifactor dimensionality reduction (MDR) and classification and regression tree analysis (CART). Overall, a protective effect was reported when a combinatorial effect of SNPs were studied by applying logistic regression analysis. Multifactor dimensionality reduction (MDR) analysis, revealed that the four factor model i.e. XPC K939Q, XPA 5'UTR, XPG F670W and XPG D1104H had the best ability to predict lung cancer risk (CVC = 100, p < 0.0001). While a two factor model, including smoking and XPG F670W suggested smoking was associated with the risk of developing lung cancer (CVC = 100, p < 0.0001). Individually XPG F670W was identified as the primary risk factor. In classification and regression tree analysis (CART), we observed a 6-fold risk for SCLC patients carrying XPA 5'UTR (M), XPD K751Q (W) (OR: 6.20; 95%CI: 2.40-16.01, p = 0.0001).Polymorphic NER genes might jointly modulate lung cancer risk through gene-gene and gene-smoking interaction.
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Affiliation(s)
- Shweta Lawania
- Department of Biotechnology, Thapar University, Punjab, 147002, India
| | - Amrita Singh
- Department of Biotechnology, Thapar University, Punjab, 147002, India
| | - Siddharth Sharma
- Department of Biotechnology, Thapar University, Punjab, 147002, India.
| | - Navneet Singh
- Department of Pulmonary Medicine, Post Graduate Institute of Medical Education & Research (PGIMER), Sector 14, Chandigarh, India
| | - Digamber Behera
- Department of Pulmonary Medicine, Post Graduate Institute of Medical Education & Research (PGIMER), Sector 14, Chandigarh, India
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Baesse CQ, Tolentino VCDM, Morelli S, Melo C. Effect of urbanization on the micronucleus frequency in birds from forest fragments. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 171:631-637. [PMID: 30658298 DOI: 10.1016/j.ecoenv.2019.01.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 01/06/2019] [Accepted: 01/07/2019] [Indexed: 06/09/2023]
Abstract
The urbanization contributes to environment contamination, mainly by the increased vehicle traffic. This intense traffic releases in the air chemical compounds with mutagenic properties that can affect the entire ecosystem. The birds for the flight accumulate air, absorbing gases or particles. The absorption of this polluted air may be causative agent responsible for micronucleus (MN) induction in bird erythrocytes. The quantitative analysis of MN in birds can assists in the monitoring environmental quality of various places. The study aimed to quantify the MN frequency in birds and compare their variation: I) among forest fragments distant from and near to urbanization, II) among species and populations of birds and III) to find if there is a relation between vehicle traffic and MN induction. The capture of the birds took place in four forest fragments in central Brazil (two distant and two near the city) using mist nets. Blood smears were prepared with blood collected from the tarso-metatarsal vein. A total of 354 individuals were analyzed and MN were found in 52% of the individuals analyzed. All sampled birds were identified and resulted to belong to 50 different species, only 4 of which were captured in all the 4 forest fragments. The average MN frequency, regardless of bird species and sampling area, was 1.04/10,000 erythrocytes. From an overall analysis carried out on all birds, the MN frequencies were found to vary among forest fragments distant from and near to urbanization (x2 =15.513; p < 0.001) and demonstrated positive correlation between vehicle traffic intensity and the MN frequency (r = 0.988; df=2; p = 0.011). The species of birds presented variation in the amount of MN (x2 = 84.64; df=49; p = 0.001). Therefore, a restricted analysis carried out on the 4 species of birds present in all the forest fragments showed that the populations of Antilophia galeata (x2 =6.029; p = 0.014), Basileuterus culicivorus (x2 =9.53; p = 0.002), Eucometis penicillata (x2 =8.067; p = 0.005) and Myiothlypis flaveola (x2 =4.771; p = 0.029) showed difference in the MN frequency, when compared between forest fragments distant from and near to cities. The analysis demonstrated that birds living in forest areas near to the city presented higher MN frequency, probably because pollutants generated by urbanization affect birds and that the larger the vehicle traffic the greater the induced MN in the birds.
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Affiliation(s)
- Camilla Queiroz Baesse
- Federal University of Uberlândia, Institute of Biology, Laboratory of Ornithology and Bioacoustics, Umuarama Campus, Rua Ceará, s/n, 38400-902 Uberlândia, Minas Gerais, Brazil; Federal University of Uberlândia, Institute of Genetics and Biochemistry, Cytogenetic and Mutagenesis Laboratory, Umuarama Campus, Avenida Pará 1720, 38400-902 Uberlândia, Minas Gerais, Brazil; Postgraduate Program in Genetics and Biochemistry, Federal University of Uberlândia, Brazil.
| | - Vitor Carneiro de Magalhães Tolentino
- Federal University of Uberlândia, Institute of Biology, Laboratory of Ornithology and Bioacoustics, Umuarama Campus, Rua Ceará, s/n, 38400-902 Uberlândia, Minas Gerais, Brazil; Postgraduate Program in Ecology and Conservation of Natural Resources, Federal University of Uberlândia, Brazil
| | - Sandra Morelli
- Federal University of Uberlândia, Institute of Genetics and Biochemistry, Cytogenetic and Mutagenesis Laboratory, Umuarama Campus, Avenida Pará 1720, 38400-902 Uberlândia, Minas Gerais, Brazil
| | - Celine Melo
- Federal University of Uberlândia, Institute of Biology, Laboratory of Ornithology and Bioacoustics, Umuarama Campus, Rua Ceará, s/n, 38400-902 Uberlândia, Minas Gerais, Brazil
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Abstract
While spontaneous tumours may occasionally develop in inbred and isogenic strains of Xenopus laevis, the South African clawed toad, they are extremely rare in natural and laboratory populations. Only two amphibian neoplasms, the renal adenocarcinoma of Rana pipiens and the lymphosarcoma of Xenopus laevis, have been extensively explored. Amphibians are resistant to the development of neo-plasia, even following exposure to “direct-acting” chemical carcinogens such as N-methyl- N-nitrosourea, that are highly lymphotoxic, thus diminishing immune reactivity. Regenerative capacity in adults, and a dramatic metamorphosis which remodels much of the larval body to produce the adult form, are unique to amphibian vertebrates, and the control mechanisms involved may protect against cancer. For example, naturally rising corticosteroid titres during metamorphosis will impair some T-cell functions, and the removal of T-regulatory (suppressor) functions inhibits the induction of altered-self tolerance. Altered-self tolerance is not as effectively induced in adult Xenopus laevis as in mammals, so cancer cells with new antigenicity are more likely be rejected in amphibians. Amphibian immunocytes tend to undergo apoptosis readily in vitro, and, unlike mammalian immunocytes, undergo apoptosis without entering the cell cycle. Cells not in the cell cycle that die from nuclear damage (apoptosis), will have no opportunity to express genetic instability leading to cell transformation. We suggest that all these factors, rather than any one of them, may reduce susceptibility to cancer in amphibians.
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Affiliation(s)
| | - Richard H. Clothier
- School of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
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Mycoplasma promotes malignant transformation in vivo, and its DnaK, a bacterial chaperone protein, has broad oncogenic properties. Proc Natl Acad Sci U S A 2018; 115:E12005-E12014. [PMID: 30509983 PMCID: PMC6304983 DOI: 10.1073/pnas.1815660115] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
We provide evidence here that (i) a strain of mycoplasma promotes lymphomagenesis in an in vivo mouse model; (ii) a bacterial chaperone protein, DnaK, is likely implicated in the transformation process and resistance to anticancer drugs by interfering with important pathways related to both DNA-damage control/repair and cell-cycle/apoptosis; and (iii) a very low copy number of DNA sequences of mycoplasma DnaK were found in some tumors of the infected mice. Other tumor-associated bacteria carry a similar DnaK protein. Our data suggest a common mechanism whereby bacteria can be involved in cellular transformation and resistance to anticancer drugs by a hit-and-hide/run mechanism. We isolated a strain of human mycoplasma that promotes lymphomagenesis in SCID mice, pointing to a p53-dependent mechanism similar to lymphomagenesis in uninfected p53−/− SCID mice. Additionally, mycoplasma infection in vitro reduces p53 activity. Immunoprecipitation of p53 in mycoplasma-infected cells identified several mycoplasma proteins, including DnaK, a member of the Hsp70 chaperon family. We focused on DnaK because of its ability to interact with proteins. We demonstrate that mycoplasma DnaK interacts with and reduces the activities of human proteins involved in critical cellular pathways, including DNA-PK and PARP1, which are required for efficient DNA repair, and binds to USP10 (a key p53 regulator), impairing p53-dependent anticancer functions. This also reduced the efficacy of anticancer drugs that depend on p53 to exert their effect. mycoplasma was detected early in the infected mice, but only low copy numbers of mycoplasma DnaK DNA sequences were found in some primary and secondary tumors, pointing toward a hit-and-run/hide mechanism of transformation. Uninfected bystander cells took up exogenous DnaK, suggesting a possible paracrine function in promoting malignant transformation, over and above cells infected with the mycoplasma. Phylogenetic amino acid analysis shows that other bacteria associated with human cancers have similar DnaKs, consistent with a common mechanism of cellular transformation mediated through disruption of DNA-repair mechanisms, as well as p53 dysregulation, that also results in cancer-drug resistance. This suggests that the oncogenic properties of certain bacteria are DnaK-mediated.
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Viswanathan S, Kanagaraj K, Raavi V, Dhanasekaran S, Panicker VK, R K, S Balajee A, Perumal V. Does proliferation capacity of lymphocytes depend on human blood types? J Cell Biochem 2018; 120:5722-5728. [PMID: 30320915 DOI: 10.1002/jcb.27858] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 09/19/2018] [Indexed: 12/18/2022]
Abstract
In vitro human lymphocyte culture methodology is well established yet certain confounding factors such as age, medical history as well as individual's blood type may potentially modulate in vitro proliferation response. These factors have to be carefully evaluated to release reliable test report in routine cytogenetic evaluation for various genetic conditions, radiation biodosimetry, etc. With this objective, the current study was focused on analyzing the proliferation response of lymphocytes drawn from 90 individuals (21-29 years) with different blood types. The proliferation response was assessed in the cultured lymphocytes by cell cycle, mitotic index (MI), and nuclear division index (NDI) after stimulation with phytohaemagglutinin (PHA). To investigate the toxic effect on proliferation, MI was calculated in representative samples of each blood type were X-irradiated. The results showed that there was no significant difference among the cell cycle phases of lymphocytes in different blood types (P > 0.05). Similarly, both MI and NDI of lymphocytes derived from different blood types also did not show significant difference ( P > 0.05). The extensive interindividual variation within and among the blood types is likely responsible for the lack of significant difference in lymphocyte proliferation. Although spontaneous proliferation efficiency of lymphocytes of different blood types after PHA stimulation was grossly similar, the MI observed after radiation exposure showed a significant difference ( P < 0.05) indicating a differential proliferation response among the blood types. Our results suggest that the blood types did not have any impact on PHA-induced proliferation; however, a specific differential lymphocyte proliferation observed after radiation exposure needs to be considered.
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Affiliation(s)
- Sribala Viswanathan
- Department of Human Genetics, Sri Ramachandra Medical College and Research Institute (Deemed to be University), Porur, India
| | - Karthik Kanagaraj
- Department of Human Genetics, Sri Ramachandra Medical College and Research Institute (Deemed to be University), Porur, India
| | - Venkateswarlu Raavi
- Department of Human Genetics, Sri Ramachandra Medical College and Research Institute (Deemed to be University), Porur, India
| | - Shanmugapriya Dhanasekaran
- Department of Human Genetics, Sri Ramachandra Medical College and Research Institute (Deemed to be University), Porur, India
| | - Vinod Kumar Panicker
- Department of Transfusion Medicine, Sri Ramachandra Medical College & Research Institute (Deemed to be University), Porur, India
| | - Krishnamoorthy R
- Department of Transfusion Medicine, Sri Ramachandra Medical College & Research Institute (Deemed to be University), Porur, India
| | - Adayabalam S Balajee
- Cytogenetics Biodosimetry Laboratory, REAC/TS, Oak Ridge Associated Universities, Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee
| | - Venkatachalam Perumal
- Department of Human Genetics, Sri Ramachandra Medical College and Research Institute (Deemed to be University), Porur, India
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Silvestrov P, Maier SJ, Fang M, Cisneros GA. DNArCdb: A database of cancer biomarkers in DNA repair genes that includes variants related to multiple cancer phenotypes. DNA Repair (Amst) 2018; 70:10-17. [PMID: 30098577 PMCID: PMC6151283 DOI: 10.1016/j.dnarep.2018.07.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 07/30/2018] [Accepted: 07/30/2018] [Indexed: 02/04/2023]
Abstract
Functioning DNA repair capabilities are vital for organisms to ensure that the biological information is preserved and correctly propagated. Disruptions in DNA repair pathways can result in the accumulation of DNA mutations, which may lead to onset of complex disease such as cancer. The discovery and characterization of cancer-related biomarkers may allow early diagnosis and targeted treatment, which could significantly contribute to the survival rates of cancer patients. To this end, we have applied a hypothesis driven bioinformatics approach to identify biomarkers related to 25 different DNA repair enzymes, in combination with structural analysis of six selected missense mutations of newly discovered SNPs that are associated with cancer phenotypes. Our search on 8 distinct cancer databases uncovered 43 missense SNPs that statistically significantly associated at least one phenotype. Moreover, nine of these missense SNPs are statistically significantly associated with two or more cancers. In addition, we have performed classical molecular dynamics to characterize the impact of rs10018786 on POLN, which results in the M310 L Pol ν variant, and rs3218784 on POLI, which results in the I236 M Pol ι. Our results suggest that both of these cancer-associated variants result in noticeable structural and dynamical changes compared with their respective wild-type proteins.
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Affiliation(s)
- Pavel Silvestrov
- Department of Chemistry, University of North Texas, Denton, TX, 76201, United States
| | - Sarah J Maier
- Department of Chemistry, University of North Texas, Denton, TX, 76201, United States
| | - Michelle Fang
- Department of Chemistry, University of North Texas, Denton, TX, 76201, United States
| | - G Andrés Cisneros
- Department of Chemistry, University of North Texas, Denton, TX, 76201, United States.
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Nogueira GAS, Costa EFD, Lopes-Aguiar L, Lima TRP, Visacri MB, Pincinato EC, Lourenço GJ, Calonga L, Mariano FV, Altemani AMDAM, Altemani JMC, Moriel P, Chone CT, Ramos CD, Lima CSP. Polymorphisms in DNA mismatch repair pathway genes predict toxicity and response to cisplatin chemoradiation in head and neck squamous cell carcinoma patients. Oncotarget 2018; 9:29538-29547. [PMID: 30038702 PMCID: PMC6049861 DOI: 10.18632/oncotarget.25268] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 03/26/2018] [Indexed: 12/27/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is treated with cisplatin (CDDP) and radiotherapy (RT), and distinct results are observed among patients with similar clinicopathological aspects. This prospective study aimed to investigate whether MLH1 c.-93G>A (rs1800734), MSH2 c.211+9C>G (rs2303426), MSH3 c.3133G>A (rs26279), EXO1 c.1765G>A (rs1047840), and EXO1 c.2270C>T (rs9350) single nucleotide polymorphisms (SNPs) of the mismatch repair (MMR) pathway change side effects and response rate of 90 HNSCC patients treated with CDDP and RT. DNA from peripheral blood was analyzed by PCR-based methods to obtain genotypes. It was observed 4.27-fold and 4.69-fold increased risks of presenting pronounced nephrotoxicity with treatment in patients with MSH3 GG and EXO1 rs9350 CC genotypes compared with patients with GA or AA and CT or TT genotypes, respectively. MSH3 GG or GA and GT haplotype of EXO1 rs1047840 and rs9350 SNPs conferred to patients 10.29 and 4.00 more chances of presenting pronounced ototoxicity after treatment than MSH3 AA genotype and other EXO1 haplotypes, respectively. Patients with EXO1 rs1047840 GA or AA genotype and AC haplotype of EXO1 rs1047840 and rs9350 SNPs had both 9.55-fold increased risks of achieving partial response or stable disease instead of complete remission after treatment than patients with EXO1 GG genotype and other EXO1 haplotypes, respectively. For the first time, our data show preliminary indication that inherited alterations of DNA MMR pathway, related to MSH3 rs26279, EXO1 rs1047840 and EXO1 rs9350 SNPs, modify toxicity and response to chemoradiation in HNSCC, and may contribute to future personalized treatment of patients.
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Affiliation(s)
| | | | - Leisa Lopes-Aguiar
- Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Tathiane Regine Penna Lima
- Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Marília Berlofa Visacri
- Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Eder Carvalho Pincinato
- Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Gustavo Jacob Lourenço
- Laboratory of Cancer Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Luciane Calonga
- Department of Ophthalmology and Otorhinolaryngology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Fernanda Viviane Mariano
- Department of Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | | | | | - Patrícia Moriel
- Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Carlos Takahiro Chone
- Department of Ophthalmology and Otorhinolaryngology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Celso Dario Ramos
- Department of Radiology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
| | - Carmen Silvia Passos Lima
- Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil
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ERCC1 rs11615 polymorphism increases susceptibility to breast cancer: a meta-analysis of 4547 individuals. Biosci Rep 2018; 38:BSR20180440. [PMID: 29752341 PMCID: PMC6013698 DOI: 10.1042/bsr20180440] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 05/06/2018] [Accepted: 05/10/2018] [Indexed: 12/12/2022] Open
Abstract
Excision repair cross-complementation group 1 (ERCC1), a DNA repair protein, is vital for maintaining genomic fidelity and integrity. Despite the fact that a mounting body of case-control studies has concentrated on investigating the association of the ERCC1 rs11615 polymorphism and breast cancer risk, there is still no consensus on it. We conducted the current meta-analysis of all eligible articles to reach a much more explicit conclusion on this ambiguous association. A total of seven studies involving 2354 breast cancer cases and 2193 controls were elaborately selected for this analysis from the Embase, EBSCO, PubMed, WanFang, and China National Knowledge Infrastructure (CNKI) databases. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated in our meta-analysis. We found that the ERCC1 rs11615 polymorphism was significantly associated with breast cancer risk under all genetic models. When excluded, the studies that deviated from Hardy-Weinberg equilibrium (HWE), the pooled results of what remained significantly increase the risk of breast cancer under the allele model (OR = 1.14, 95% CI = 1.02-1.27, P=0.02), heterozygote model (OR = 1.24, 95% CI = 1.06-1.44, P=0.007), and dominant model (OR = 1.21, 95% CI = 1.05-1.41, P=0.01). This increased breast cancer risk was found in Asian population as well as under the heterozygote model (OR = 1.24, 95% CI = 1.05-1.48, P=0.013) and dominant model (OR = 1.20, 95% CI = 1.02-1.42, P=0.03). Our results suggest that the ERCC1 rs11615 polymorphism is associated with breast cancer susceptibility, and in particular, this increased risk of breast cancer existence in Asian population.
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Kuykendall A, Duployez N, Boissel N, Lancet JE, Welch JS. Acute Myeloid Leukemia: The Good, the Bad, and the Ugly. Am Soc Clin Oncol Educ Book 2018; 38:555-573. [PMID: 30231330 DOI: 10.1200/edbk_199519] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Acute myeloid leukemia (AML) was initially subdivided according to morphology (the French-American-British system), which proved helpful in pathologic categorization. Subsequently, clinical and genomic factors were found to correlate with response to chemotherapy and with overall survival. These included a history of antecedent hematologic disease, a history of chemotherapy or radiation therapy, the presence of various recurrent cytogenetic abnormalities, and, more recently, the presence of specific point mutations. This article reviews the biology and responses of one AML subgroup with consistent response and good outcomes following chemotherapy (core-binding factor leukemia), and two subgroups with persistently bad, and even ugly, outcomes (secondary AML and TP53-mutated AML).
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MESH Headings
- Alleles
- Biomarkers, Tumor
- Chromosome Aberrations
- Combined Modality Therapy
- Core Binding Factors/genetics
- Core Binding Factors/metabolism
- Gene Frequency
- Humans
- Leukemia, Myeloid, Acute/diagnosis
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/etiology
- Leukemia, Myeloid, Acute/mortality
- Mutation
- Neoplasm, Residual/diagnosis
- Neoplasms, Second Primary/diagnosis
- Neoplasms, Second Primary/epidemiology
- Neoplasms, Second Primary/etiology
- Neoplasms, Second Primary/therapy
- Signal Transduction
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
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Affiliation(s)
- Andrew Kuykendall
- From the Moffitt Cancer Center, Tampa, FL; CHU Lille, INSERM, Laboratory of Hematology, University of Lille, Lille, France; Hematology Department, Saint-Louis Hospital, Paris Diderot University, Paris, France; Washington University School of Medicine, St. Louis, MO
| | - Nicolas Duployez
- From the Moffitt Cancer Center, Tampa, FL; CHU Lille, INSERM, Laboratory of Hematology, University of Lille, Lille, France; Hematology Department, Saint-Louis Hospital, Paris Diderot University, Paris, France; Washington University School of Medicine, St. Louis, MO
| | - Nicolas Boissel
- From the Moffitt Cancer Center, Tampa, FL; CHU Lille, INSERM, Laboratory of Hematology, University of Lille, Lille, France; Hematology Department, Saint-Louis Hospital, Paris Diderot University, Paris, France; Washington University School of Medicine, St. Louis, MO
| | - Jeffrey E Lancet
- From the Moffitt Cancer Center, Tampa, FL; CHU Lille, INSERM, Laboratory of Hematology, University of Lille, Lille, France; Hematology Department, Saint-Louis Hospital, Paris Diderot University, Paris, France; Washington University School of Medicine, St. Louis, MO
| | - John S Welch
- From the Moffitt Cancer Center, Tampa, FL; CHU Lille, INSERM, Laboratory of Hematology, University of Lille, Lille, France; Hematology Department, Saint-Louis Hospital, Paris Diderot University, Paris, France; Washington University School of Medicine, St. Louis, MO
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Polymorphic Variation in Double Strand Break Repair Gene in Indian Population: A Comparative Approach with Worldwide Ethnic Group Variations. Indian J Clin Biochem 2018; 33:184-189. [PMID: 29651209 DOI: 10.1007/s12291-017-0665-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 05/09/2017] [Indexed: 10/19/2022]
Abstract
DNA repair capacity is essential in maintaining cellular functions and homeostasis. Identification of genetic polymorphisms responsible for reduced DNA repair capacity may allow better cancer prevention. Double strand break repair pathway plays critical roles in maintaining genome stability. Present study was conducted to determine distribution of XRCC3 Exon 7 (C18067T, rs861539) and XRCC7 Intron 8 (G6721T, rs7003908) gene polymorphisms in North Indian population and compare with different populations globally. The genotype assays were performed in 224 normal healthy individuals of similar ethnicity using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Allelic frequencies of wild type were 79% (C) in XRCC3 Exon 7 C > T and 57% (G) in XRCC7 Intron 8 (G > T) 57% (G) observed. On the other hand, the variant allele frequency were 21% (T) in XRCC3 Exon 7 C > T and 43% (T) in XRCC7 Intron 8 G > T respectively. Major differences from other ethnic populations were observed. Our results suggest that frequency in these DNA repair genes exhibit distinctive pattern in India that could be attributed to ethnicity variation. This could assist in high-risk screening of humans exposed to environmental carcinogens and cancer predisposition in different ethnic groups.
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26
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XRCC1 Arg194Trp polymorphism is no risk factor for skin cancer development in Kashmiri population. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2018. [DOI: 10.1016/j.ejmhg.2017.07.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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27
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APE1 polymorphic variants cause persistent genomic stress and affect cancer cell proliferation. Oncotarget 2018; 7:26293-306. [PMID: 27050370 PMCID: PMC5041981 DOI: 10.18632/oncotarget.8477] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 03/12/2016] [Indexed: 01/15/2023] Open
Abstract
Apurinic/apyrimidinic endonuclease 1 (APE1) is the main mammalian AP-endonuclease responsible for the repair of endogenous DNA damage through the base excision repair (BER) pathway. Molecular epidemiological studies have identified several genetic variants associated with human diseases, but a well-defined functional connection between mutations in APE1 and disease development is lacking. In order to understand the biological consequences of APE1 genetic mutations, we examined the molecular and cellular consequences of the selective expression of four non-synonymous APE1 variants (L104R, R237C, D148E and D283G) in human cells. We found that D283G, L104R and R237C variants have reduced endonuclease activity and impaired ability to associate with XRCC1 and DNA polymerase β, which are enzymes acting downstream of APE1 in the BER pathway. Complementation experiments performed in cells, where endogenous APE1 had been silenced by shRNA, showed that the expression of these variants resulted in increased phosphorylation of histone H2Ax and augmented levels of poly(ADP-ribosyl)ated (PAR) proteins. Persistent activation of DNA damage response markers was accompanied by growth defects likely due to combined apoptotic and autophagic processes. These phenotypes were observed in the absence of exogenous stressors, suggesting that chronic replication stress elicited by the BER defect may lead to a chronic activation of the DNA damage response. Hence, our data reinforce the concept that non-synonymous APE1 variants present in the human population may act as cancer susceptibility alleles.
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Erdal S, McCarthy BJ, Gurule N, Berwick M, Gonzales E, Byrd J, Flores K, Shimek J, Il'yasova D, Ali-Osman F, Bigner DD, Davis FG, Leyba AN, White KAM. Application of mutagen sensitivity assay in a glioma case-control study. Toxicol Rep 2018; 5:183-188. [PMID: 29854587 PMCID: PMC5977159 DOI: 10.1016/j.toxrep.2017.12.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 12/07/2017] [Accepted: 12/08/2017] [Indexed: 12/03/2022] Open
Abstract
MSA is an appropriate molecular epidemiology tool in case control studies. Case-control status/exposure categories are not associated with the number of breaks. Cell lines of glioma patients did not show reduced DNA repair capacity in response to acrylamide in the MSA assay. Few risk factors for glioma have been identified other than ionizing radiation. The alkylating agent acrylamide is a compound found in both occupational and the general environment and identified as one of the forty known or suspected neurocarcinogens in animal models. The mutagen sensitivity assay (MSA) has been used to indirectly show reduced DNA repair capacity upon exposure to ionizing radiation in those with glioma compared to controls. In this study, MSA was used to assess its applicability to a glioma case-control study and to test the hypothesis that subjects with glioma may have lower DNA repair capacity after exposure to selected potential human neurocarcinogens (i.e. acrylamide), compared to controls. Approximately 50 case and 50 control subjects were identified from a clinic-based study that investigated environmental risk factors for glioma, who completed an exposure survey, and had frozen immortalized lymphocytes available. A total of 50 metaphase spreads were read and reported for each participant. The association of case-control status with MSA for acrylamide, i.e. breaks per spread, was examined by multivariable logistic regression models. The mean number of breaks per slide was similar between hospital-based controls and cases. In addition, case-control status or exposure categories were not associated with the number of breaks per spread. Although the MSA has been shown as a useful molecular epidemiology tool for identifying individuals at higher risk for cancer, our data do not support the hypothesis that glioma patients have reduced DNA repair capacity in response to exposure to acrylamide. Further research is needed before the MSA is utilized in large-scale epidemiological investigations of alkylating agents.
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Affiliation(s)
- Serap Erdal
- Divisions of Environmental, Occupational Health Science, University of Illinois at Chicago, Chicago, IL, United States
| | - Bridget J McCarthy
- Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, IL, United States.,University of Illinois at Chicago Cancer Center, University of Illinois at Chicago, Chicago, IL, United States
| | - Natalia Gurule
- Department of Cancer Biology, University of Colorado Anschutz Medical Campus, United States
| | - Marianne Berwick
- Molecular Epidemiology Lab, University of New Mexico, Albuquerque, NM, United States.,Division of Epidemiology, University of New Mexico, Albuquerque, NM, United States
| | - Emily Gonzales
- Molecular Epidemiology Lab, University of New Mexico, Albuquerque, NM, United States
| | - Johanna Byrd
- Molecular Epidemiology Lab, University of New Mexico, Albuquerque, NM, United States
| | - Kristina Flores
- UNM Cancer Center, University of New Mexico, Albuquerque, NM, United States
| | - JoAnna Shimek
- Department of Environmental Health, Indiana University Bloomington, IN, United States
| | - Dora Il'yasova
- Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC, United States.,Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, United States
| | - Francis Ali-Osman
- Department of Surgery, Duke University Medical Center, Durham, NC, United States.,Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC, United States.,Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, United States.,Pediatric Brain Tumor Foundation Institute at Duke, Duke University Medical Center, Durham, NC, United States
| | - Darell D Bigner
- Department of Pathology, Duke University Medical Center, Durham, NC, United States.,Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC, United States.,Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, United States.,Pediatric Brain Tumor Foundation Institute at Duke, Duke University Medical Center, Durham, NC, United States
| | - Faith G Davis
- Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, IL, United States.,University of Illinois at Chicago Cancer Center, University of Illinois at Chicago, Chicago, IL, United States.,School of Public Health, University of Alberta, Edmonton, Alberta, Canada
| | - Alexis N Leyba
- UNM Cancer Center, University of New Mexico, Albuquerque, NM, United States
| | - Kirsten A M White
- Molecular Epidemiology Lab, University of New Mexico, Albuquerque, NM, United States
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Tao J, Zhuo ZJ, Su M, Yan L, He J, Zhang J. XPA gene polymorphisms and risk of neuroblastoma in Chinese children: a two-center case-control study. J Cancer 2018; 9:2751-2756. [PMID: 30087717 PMCID: PMC6072815 DOI: 10.7150/jca.25973] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 06/09/2018] [Indexed: 02/07/2023] Open
Abstract
Neuroblastoma is a malignant tumor arising from the developing sympathetic nervous system, which mainly affects children. Variations in XPA gene have been shown to confer cancer susceptibility. However, no investigation has been reported regarding the association between XPA polymorphisms and neuroblastoma risk. This study was conducted to measure the association of XPA polymorphisms with neuroblastoma susceptibility in Chinese children. In this hospital-based case-control study with 393 cases and 812 controls, we genotyped two polymorphisms (rs1800975 T>C, and rs3176752 G>T) in XPA gene to access their contributions to neuroblastoma risk by TaqMan methods. The strength of the association with neuroblastoma risk was estimated by odds ratios (ORs) and 95% confidence intervals (CIs). No single polymorphism was found to predispose to neuroblastoma susceptibility. When risk genotypes were combined, we found that carriers of 1-2 risk genotypes had significantly increased neuroblastoma risk (adjusted OR=1.28; 95% CI=1.001-1.64, P=0.049), when compared to non-carriers. Stratification analysis by age, gender, sites of origin and clinical stages failed to show any significant association. Our study provides cues that XPA gene polymorphisms may exert a weak effect in neuroblastoma risk. This finding needs further validations by larger sample size studies.
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Affiliation(s)
- Jing Tao
- Department of Pathology, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou 450053, Henan, China
| | - Zhen-Jian Zhuo
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Meng Su
- Department of Pediatric Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Lizhao Yan
- Department of Pediatric Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
- ✉ Corresponding authors: Jiao Zhang, Department of Pediatric Surgery, the First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou 450052, Henan, China, Tel./Fax: (+86- 0371) 66279071, ; or Jing He, Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou 510623, Guangdong, China, Tel./Fax: (+86-020) 38076560,
| | - Jiao Zhang
- Department of Pediatric Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
- ✉ Corresponding authors: Jiao Zhang, Department of Pediatric Surgery, the First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou 450052, Henan, China, Tel./Fax: (+86- 0371) 66279071, ; or Jing He, Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou 510623, Guangdong, China, Tel./Fax: (+86-020) 38076560,
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Wu Y, Lu ZP, Zhang JJ, Liu DF, Shi GD, Zhang C, Qin ZQ, Zhang JZ, He Y, Wu PF, Miao Y, Jiang KR. Association between ERCC2 Lys751Gln polymorphism and the risk of pancreatic cancer, especially among Asians: evidence from a meta-analysis. Oncotarget 2017; 8:50124-50132. [PMID: 28223548 PMCID: PMC5564835 DOI: 10.18632/oncotarget.15394] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 01/29/2017] [Indexed: 12/21/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) of Excision repair cross-complementing group 2 (ERCC2) gene are suspected to affect the risk of pancreatic cancer. Many studies have reported the association between ERCC2 Lys751Gln polymorphism (rs13181) and the susceptibility to pancreatic cancer, but the outcomes remained controversial. To comprehensively determine this association, we conducted a meta-analysis based on a total of eight studies. Evidence for this association was obtained from the PubMed, EMBASE, Web of Science and Chinese National Knowledge Infrastructure (CNKI) databases. In general, a significant association was found between ERCC2 rs13181 polymorphism and the susceptibility to pancreatic cancer in four genetic models [CC vs. AA: OR = 1.56, (95% CI: 1.28-1.90), P = 0.470; AC/CC vs. AA: OR=1.20, (95% CI: 1.06-1.36), P = 0.396; CC vs. AC/CC OR = 1.50; (95% CI: 1.24-1.81), P = 0.530; C vs. A: OR=1.22, (95%CI:1.11-1.34), P = 0.159]. Furthermore, stratified analyses by ethnicity indicated a significant association only in the Asian population. Our results indicate that the ERCC2 Lys751Gln polymorphism might be important in stimulating the development of pancreatic cancer, especially for Asians.
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Affiliation(s)
- Yang Wu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Zi-Peng Lu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Jing-Jing Zhang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Dong-Fang Liu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Guo-Dong Shi
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Chun Zhang
- Department of Digestive Diseases, Songjiang Branch Hospital of Shanghai First People's Hospital, Nanjing Medical University, Shanghai, China
| | - Zhi-Qiang Qin
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian-Zhong Zhang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuan He
- Pancreas Institute, Nanjing Medical University, Nanjing, China.,Department of Gastrointestinal Surgery, Huai'an Affiliated to Xuzhou Medical University and Huai'an Second People's Hospital, Huai'an, China
| | - Peng-Fei Wu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yi Miao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Kui-Rong Jiang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
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Buckley AR, Standish KA, Bhutani K, Ideker T, Lasken RS, Carter H, Harismendy O, Schork NJ. Pan-cancer analysis reveals technical artifacts in TCGA germline variant calls. BMC Genomics 2017; 18:458. [PMID: 28606096 PMCID: PMC5467262 DOI: 10.1186/s12864-017-3770-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 05/07/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Cancer research to date has largely focused on somatically acquired genetic aberrations. In contrast, the degree to which germline, or inherited, variation contributes to tumorigenesis remains unclear, possibly due to a lack of accessible germline variant data. Here we called germline variants on 9618 cases from The Cancer Genome Atlas (TCGA) database representing 31 cancer types. RESULTS We identified batch effects affecting loss of function (LOF) variant calls that can be traced back to differences in the way the sequence data were generated both within and across cancer types. Overall, LOF indel calls were more sensitive to technical artifacts than LOF Single Nucleotide Variant (SNV) calls. In particular, whole genome amplification of DNA prior to sequencing led to an artificially increased burden of LOF indel calls, which confounded association analyses relating germline variants to tumor type despite stringent indel filtering strategies. The samples affected by these technical artifacts include all acute myeloid leukemia and practically all ovarian cancer samples. CONCLUSIONS We demonstrate how technical artifacts induced by whole genome amplification of DNA can lead to false positive germline-tumor type associations and suggest TCGA whole genome amplified samples be used with caution. This study draws attention to the need to be sensitive to problems associated with a lack of uniformity in data generation in TCGA data.
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Affiliation(s)
- Alexandra R Buckley
- Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.,J. Craig Venter Institute, La Jolla, CA, USA
| | - Kristopher A Standish
- Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.,J. Craig Venter Institute, La Jolla, CA, USA
| | - Kunal Bhutani
- Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.,Bioinformatics and Systems Biology Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA
| | - Trey Ideker
- Division of Medical Genetics, Department of Medicine, University of California San Diego, La Jolla, CA, USA.,Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.,Cancer Cell Map Initiative (CCMI), University of California San Diego, La Jolla, CA, USA
| | - Roger S Lasken
- Microbial Genomics Program, J. Craig Venter Institute, La Jolla, CA, USA
| | - Hannah Carter
- Division of Medical Genetics, Department of Medicine, University of California San Diego, La Jolla, CA, USA.,Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.,Cancer Cell Map Initiative (CCMI), University of California San Diego, La Jolla, CA, USA
| | - Olivier Harismendy
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.,Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Nicholas J Schork
- J. Craig Venter Institute, La Jolla, CA, USA. .,The Translational Genomics Research Institute, Phoenix, AZ, USA.
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32
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Santovito A, Delsoglio M, Manitta E, Picco G, Meschiati G, Chiarizio M, Gendusa C, Cervella P. Association of GSTT1 null, XPD 751 CC and XPC 939 CC genotypes with increased levels of genomic damage among hospital pathologists. Biomarkers 2017; 22:557-565. [PMID: 28434254 DOI: 10.1080/1354750x.2017.1322147] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
CONTEXT Hospital workers are at risk for genotoxic damage following occupationally exposure to xenobiotics. Pathologists are exposed to chemicals during their use in health care environments, particularly throughout inhalation of airborne agents, absorption through skin or contact with the patient's body fluids. OBJECTIVE We evaluated the level of genomic damage in a sample of 61 hospital pathologists (occupationally exposed to antineoplastic drugs and sterilizing agents) and 60 control subjects. MATERIALS AND METHODS Lymphocytes were analyzed by SCEs and CAs assays and genotyped for GSTT1, GSTM1, CYP1A1 Ile/Val, XPD (A751C) and XPC (A939C) gene polymorphisms. RESULTS Pathologists showed significantly higher frequencies of SCEs and CAs with respect to control subjects. GSTT1 null genotype was found to be associated with higher SCEs and CAs frequencies, whereas XPD 751 CC and XPC 939 CC genotypes only with a higher level of SCEs. DISCUSSION AND CONCLUSIONS The SCEs and CAs results are consistent with other published data, placing hospital workers as a category at risk for genotoxic damage caused by chronic exposure to xenobiotics. The higher levels of cytogenetic damage observed among GSTT1 null, XPD 751 and XPC 939 CC homozygote subjects confirm the importance of the genetic polymorphisms analysis associated to genotoxicological studies.
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Affiliation(s)
- Alfredo Santovito
- a Department of Life Sciences and Systems Biology , University of Turin , Torino , Italy
| | - Marta Delsoglio
- a Department of Life Sciences and Systems Biology , University of Turin , Torino , Italy
| | - Eleonora Manitta
- a Department of Life Sciences and Systems Biology , University of Turin , Torino , Italy
| | - Giulia Picco
- a Department of Life Sciences and Systems Biology , University of Turin , Torino , Italy
| | - Giulia Meschiati
- a Department of Life Sciences and Systems Biology , University of Turin , Torino , Italy
| | - Michela Chiarizio
- a Department of Life Sciences and Systems Biology , University of Turin , Torino , Italy
| | - Claudio Gendusa
- a Department of Life Sciences and Systems Biology , University of Turin , Torino , Italy
| | - Piero Cervella
- a Department of Life Sciences and Systems Biology , University of Turin , Torino , Italy
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33
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Boege F. Comment on Shahadevan et al. "The relationship of single strand breaks in DNA to breast cancer risk and to tissue concentrations of oestrogens". Biomarkers 2017; 22:698-699. [PMID: 28286966 DOI: 10.1080/1354750x.2017.1306755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Fritz Boege
- a Institute of Clinical Chemistry and Laboratory Diagnostics , University Hospital , Düsseldorf , Germany
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34
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Munnia A, Giese RW, Polvani S, Galli A, Cellai F, Peluso MEM. Bulky DNA Adducts, Tobacco Smoking, Genetic Susceptibility, and Lung Cancer Risk. Adv Clin Chem 2017. [PMID: 28629590 DOI: 10.1016/bs.acc.2017.01.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The generation of bulky DNA adducts consists of conjugates formed between large reactive electrophiles and DNA-binding sites. The term "bulky DNA adducts" comes from early experiments that employed a 32P-DNA postlabeling approach. This technique has long been used to elucidate the association between adducts and carcinogen exposure in tobacco smoke studies and assess the predictive value of adducts in cancer risk. Molecular data showed increased DNA adducts in respiratory tracts of smokers vs nonsmokers. Experimental studies and meta-analysis demonstrated that the relationship between adducts and carcinogens was linear at low doses, but reached steady state at high exposure, possibly due to metabolic and DNA repair pathway saturation and increased apoptosis. Polymorphisms of metabolic and DNA repair genes can increase the effects of environmental factors and confer greater likelihood of adduct formation. Nevertheless, the central question remains as to whether bulky adducts cause human cancer. If so, lowering them would reduce cancer incidence. Pooled and meta-analysis has shown that smokers with increased adducts have increased risk of lung cancer. Adduct excess in smokers, especially in prospective longitudinal studies, supports their use as biomarkers predictive of lung cancer.
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Affiliation(s)
- Armelle Munnia
- Cancer Risk Factor Branch, Regional Cancer Prevention Laboratory, ISPO-Cancer Prevention and Research Institute, Florence, Italy
| | - Roger W Giese
- Bouve College of Health Sciences, Barnett Institute, Northeastern University, Boston, MA, United States
| | - Simone Polvani
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Andrea Galli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Filippo Cellai
- Cancer Risk Factor Branch, Regional Cancer Prevention Laboratory, ISPO-Cancer Prevention and Research Institute, Florence, Italy
| | - Marco E M Peluso
- Cancer Risk Factor Branch, Regional Cancer Prevention Laboratory, ISPO-Cancer Prevention and Research Institute, Florence, Italy.
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35
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Weidele K, Beneke S, Bürkle A. The NAD + precursor nicotinic acid improves genomic integrity in human peripheral blood mononuclear cells after X-irradiation. DNA Repair (Amst) 2017; 52:12-23. [PMID: 28216063 DOI: 10.1016/j.dnarep.2017.02.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 02/02/2017] [Accepted: 02/02/2017] [Indexed: 01/07/2023]
Abstract
NAD+ is an essential cofactor for enzymes catalyzing redox-reactions as well as an electron carrier in energy metabolism. Aside from this, NAD+ consuming enzymes like poly(ADP-ribose) polymerases and sirtuins are important regulators involved in chromatin-restructuring processes during repair and epigenetics/transcriptional adaption. In order to replenish cellular NAD+ levels after cleavage, synthesis starts from precursors such as nicotinamide, nicotinamide riboside or nicotinic acid to match the need for this essential molecule. In the present study, we investigated the impact of supplementation with nicotinic acid on resting and proliferating human mononuclear blood cells with a focus on DNA damage and repair processes. We observed that nicotinic acid supplementation increased NAD+ levels as well as DNA repair efficiency and enhanced genomic stability evaluated by micronucleus test after x-ray treatment. Interestingly, resting cells displayed lower basal levels of DNA breaks compared to proliferating cells, but break-induction rates were identical. Despite similar levels of p53 protein upregulation after irradiation, higher NAD+ concentrations led to reduced acetylation of this protein, suggesting enhanced SIRT1 activity. Our data reveal that even in normal primary human cells cellular NAD+ levels may be limiting under conditions of genotoxic stress and that boosting the NAD+ system with nicotinic acid can improve genomic stability.
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Affiliation(s)
- Kathrin Weidele
- Molecular Toxicology Group, Department of Biology, University of Konstanz, Universitaetsstr. 10, 78457 Konstanz, Germany.
| | - Sascha Beneke
- Molecular Toxicology Group, Department of Biology, University of Konstanz, Universitaetsstr. 10, 78457 Konstanz, Germany.
| | - Alexander Bürkle
- Molecular Toxicology Group, Department of Biology, University of Konstanz, Universitaetsstr. 10, 78457 Konstanz, Germany.
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36
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Santovito A, Cannarsa E, Schleicherova D, Cervella P. Clastogenic effects of bisphenol A on human cultured lymphocytes. Hum Exp Toxicol 2017; 37:69-77. [PMID: 28178864 DOI: 10.1177/0960327117693069] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Bisphenol A is an endocrine disrupting compound widely used in the production of polycarbonate plastics and epoxy resins. It is ubiquitously present in the environment, mostly in aquatic environments, with consequent risks to the health of aquatic organisms and humans. In the present study, we analysed the cytogenetic effects of bisphenol A on human lymphocytes using in vitro chromosomal aberrations and micronuclei assays. Lymphocyte cultures were exposed to five different concentrations of BP-A (0.20, 0.10, 0.05, 0.02 and 0.01 μg/mL) for 24 h (for chromosomal aberrations test) and 48 h (for micronuclei test). The concentration of 0.05 µg/mL represents the reference dose established by United States Environmental Protection Agency (US EPA); 0.02 μg/mL represents the higher concentration of unconjugated BP-A found in human serum and 0.01 μg/mL represents the tolerable daily intake established by European Union. Data obtained from both assays showed significant genotoxic effects of the bisphenol A at concentrations of 0.20, 0.10 and 0.05 μg/mL, whereas at the concentration of 0.02 μg/mL, we observed only a significant increase in the micronuclei frequency. Finally, at the concentration of 0.01 μg/mL, no cytogenetic effects were observed, indicating this latter as a more tolerable concentration for human health with respect to 0.05 μg/mL, the reference dose established by US EPA.
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Affiliation(s)
- A Santovito
- Department of Life Sciences and Systems Biology, University of Turin, Albertina, Italy
| | - E Cannarsa
- Department of Life Sciences and Systems Biology, University of Turin, Albertina, Italy
| | - D Schleicherova
- Department of Life Sciences and Systems Biology, University of Turin, Albertina, Italy
| | - P Cervella
- Department of Life Sciences and Systems Biology, University of Turin, Albertina, Italy
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37
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Zhang W, Zhang Z. Associations between XRCC2 rs3218536 and ERCC2 rs13181 polymorphisms and ovarian cancer. Oncotarget 2016; 7:86621-86629. [PMID: 27863412 PMCID: PMC5349940 DOI: 10.18632/oncotarget.13361] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 10/29/2016] [Indexed: 01/11/2023] Open
Abstract
Recent studies explored XRCC2 rs3218536 and ERCC2 rs13181 polymorphisms and ovarian cancer (OC) risk. However, the association between these two single nucleotide polymorphisms and OC risk remains conflicting. Thus, we conducted a comprehensive systematic review and meta-analysis to investigate the association. We searched the databases of PubMed, and Embase. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using fixed-effect or random-effect models. 15 case-control studies published in 11 papers including 4,757 cases and 8,431 controls were included in this meta-analysis. No associations were obtained between XRCC2 rs3218536 and ERCC2 rs13181 polymorphisms and OC risk. Stratification analyses of Hardy–Weinberg equilibrium status indicated that rs3218536 polymorphism was associated with the decreased risk of OC when in analysis of combined HWE positive studies. In conclusion, this meta-analysis indicates that XRCC2 rs3218536 and ERCC2 rs13181 polymorphisms may not be associated with the risk of OC.
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Affiliation(s)
- Wei Zhang
- Department of Gynecology, Nanjing Medical University, Affiliated Hangzhou Hospital, Hangzhou First People's Hospital, 310006, Hangzhou, China
| | - Zhifen Zhang
- Department of Gynecology, Nanjing Medical University, Affiliated Hangzhou Hospital, Hangzhou First People's Hospital, 310006, Hangzhou, China
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38
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Evans SO, Jameson MB, Cursons RTM, Peters LM, Bird S, Jacobson GM. Development of a qPCR Method to Measure Mitochondrial and Genomic DNA Damage with Application to Chemotherapy-Induced DNA Damage and Cryopreserved Cells. BIOLOGY 2016; 5:biology5040039. [PMID: 27740596 PMCID: PMC5192419 DOI: 10.3390/biology5040039] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 09/27/2016] [Indexed: 11/23/2022]
Abstract
DNA damage quantitation assays such as the comet assay have focused on the measurement of total nuclear damage per cell. The adoption of PCR-based techniques to quantify DNA damage has enabled sequence- and organelle-specific assessment of DNA lesions. Here we report on an adaptation of a qPCR technique to assess DNA damage in nuclear and mitochondrial targets relative to control. Novel aspects of this assay include application of the assay to the Rotor-Gene platform with optimized DNA polymerase/fluorophore/primer set combination in a touchdown PCR protocol. Assay validation was performed using ultraviolet C radiation in A549 and THP1 cancer cell lines. A comparison was made to the comet assay applied to peripheral blood mononuclear cells, and an estimation of the effects of cryopreservation on ultraviolet C-induced DNA damage was carried out. Finally, dose responses for DNA damage were measured in peripheral blood mononuclear cells following exposure to the cytotoxic agents bleomycin and cisplatin. We show reproducible experimental outputs across the tested conditions and concordance with published findings with respect to mitochondrial and nuclear genotoxic susceptibilities. The application of this DNA damage assay to a wide range of clinical and laboratory-derived samples is both feasible and resource-efficient.
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Affiliation(s)
- Stephen O Evans
- Biomedical Research Unit, School of Science, University of Waikato Private Bag 3105, Hamilton 3240, New Zealand.
| | - Michael B Jameson
- Department of Oncology, Regional Cancer Centre, Waikato Hospital, Hamilton West 3204, New Zealand.
| | - Ray T M Cursons
- Biomedical Research Unit, School of Science, University of Waikato Private Bag 3105, Hamilton 3240, New Zealand.
| | - Linda M Peters
- Biomedical Research Unit, School of Science, University of Waikato Private Bag 3105, Hamilton 3240, New Zealand.
| | - Steve Bird
- Biomedical Research Unit, School of Science, University of Waikato Private Bag 3105, Hamilton 3240, New Zealand.
| | - Gregory M Jacobson
- Biomedical Research Unit, School of Science, University of Waikato Private Bag 3105, Hamilton 3240, New Zealand.
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39
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Gu S, Rong H, Zhang G, Kang L, Yang M, Guan H. Functional SNP in 3'-UTR MicroRNA-Binding Site of ZNF350 Confers Risk for Age-Related Cataract. Hum Mutat 2016; 37:1223-1230. [PMID: 27586871 DOI: 10.1002/humu.23073] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 08/10/2016] [Accepted: 08/29/2016] [Indexed: 12/28/2022]
Abstract
Many studies have suggested that individual susceptibility to age-related cataract (ARC) may be associated with DNA sequence polymorphisms affecting gene regulation. As DNA repair is implicated in ARC pathogenesis and single-nucleotide polymorphisms (SNPs) in the 3'-terminal untranslated region (3'-UTR) targeted by microRNAs (miRNAs) can alter the gene function, we hypothesize that the miRNA-binding SNPs (miRSNPs) in DNA double-strand break repair (DSBR) and nucleotide excision repair (NER) pathways might associate with ARC risk. We genotyped nine miRSNPs of eight genes in DSBR and NER pathways in Chinese population and found that ZNF350- rs2278414:G>A was significantly associated with ARC risk. Even though the Comet assay of cellular DNA damage indicated that all the subtypes of ARC patients had more DNA breaks in peripheral lymphocytes than the controls independent of rs2278414 genotypes, individuals carrying the variant A allele (AA and AG) had lower ZNF350 mRNA levels compared with individuals with GG genotype. Moreover, the in vitro experiment indicated that miR-21-3p and miR-150-5p specifically downregulated luciferase reporter expression in the cell lines transfected with rs2278414 A allele compared with rs2278414 G. These results suggested that the association of SNP rs2278414 with ARC might involve an altered miRNA regulation of ZNF350.
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Affiliation(s)
- Shanshan Gu
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Han Rong
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Guowei Zhang
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Lihua Kang
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Mei Yang
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Huaijin Guan
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
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40
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Liu Z, Lam N, Thiele CJ. Zinc finger transcription factor CASZ1 interacts with histones, DNA repair proteins and recruits NuRD complex to regulate gene transcription. Oncotarget 2016; 6:27628-40. [PMID: 26296975 PMCID: PMC4695013 DOI: 10.18632/oncotarget.4733] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 07/27/2015] [Indexed: 11/25/2022] Open
Abstract
The zinc finger transcription factor CASZ1 has been found to control neural fate-determination in flies, regulate murine and frog cardiac development, control murine retinal cell progenitor expansion and function as a tumor suppressor gene in humans. However, the molecular mechanism by which CASZ1 regulates gene transcription to exert these diverse biological functions has not been described. Here we identify co-factors that are recruited by CASZ1b to regulate gene transcription using co-immunoprecipitation (co-IP) and mass spectrometry assays. We find that CASZ1b binds to the nucleosome remodeling and histone deacetylase (NuRD) complex, histones and DNA repair proteins. Mutagenesis of the CASZ1b protein assay demonstrates that the N-terminus of CASZ1b is required for NuRD binding, and a poly(ADP-ribose) binding motif in the CASZ1b protein is required for histone H3 and DNA repair proteins binding. The N-terminus of CASZ1b fused to an artificial DNA-binding domain (GAL4DBD) causes a significant repression of transcription (5xUAS-luciferase assay), which could be blocked by treatment with an HDAC inhibitor. Realtime PCR results show that the transcriptional activity of CASZ1b mutants that abrogate NuRD or histone H3/DNA binding is significantly decreased. This indicates a model in which CASZ1b binds to chromatin and recruits NuRD complexes to orchestrate epigenetic-mediated transcriptional programs.
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Affiliation(s)
- Zhihui Liu
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA
| | - Norris Lam
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA
| | - Carol J Thiele
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA
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41
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Achel DG, Serafin AM, Akudugu JM. Flow cytometry-assisted quantification of γH2AX expression has potential as a rapid high-throughput biodosimetry tool. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2016; 55:349-357. [PMID: 27262315 DOI: 10.1007/s00411-016-0654-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 05/23/2016] [Indexed: 06/05/2023]
Abstract
Large-scale radiological events require immediate and accurate estimates of doses received by victims, and possibly the first responders, to assist in treatment decisions. Although there are numerous efforts worldwide to develop biodosimetric tools to adequately handle triage needs during radiological incidents, such endeavours do not seem to actively involve sub-Saharan Africa which currently has a significant level of nuclear-related activity. To initiate a similar interest in Africa, ex vivo radiation-induced γH2AX expression in peripheral blood lymphocytes from fourteen healthy donors was assessed using flow cytometry. While the technique shows potential for use as a rapid high-throughput biodosimetric tool for radiation absorbed doses up to 5 Gy, significant inter-individual differences in γH2AX expression emerged. Also, female donors exhibited higher levels of γH2AX expression than their male counterparts. To address these shortcomings, gender-based in-house dose-response curves for γH2AX induction in lymphocytes 2, 4, and 6 h after X-ray irradiation are proposed for the South African population. The obtained results show that γH2AX is a good candidate biomarker for biodosimetry, but might need some refinement and validation through further studies involving a larger cohort of donors.
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Affiliation(s)
- Daniel G Achel
- Division of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa
- Applied Radiation Biology Centre, Radiological and Medical Sciences Research Institute, Ghana Atomic Energy Commission, P.O. Box LG 80, Legon, Accra, Ghana
| | - Antonio M Serafin
- Division of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa
| | - John M Akudugu
- Division of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa.
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42
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Can the response to a platinum-based therapy be predicted by the DNA repair status in non-small cell lung cancer? Cancer Treat Rev 2016; 48:8-19. [DOI: 10.1016/j.ctrv.2016.05.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 04/04/2016] [Accepted: 05/12/2016] [Indexed: 12/17/2022]
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Mordukhovich I, Beyea J, Herring AH, Hatch M, Stellman SD, Teitelbaum SL, Richardson DB, Millikan RC, Engel LS, Shantakumar S, Steck SE, Neugut AI, Rossner P, Santella RM, Gammon MD. Polymorphisms in DNA repair genes, traffic-related polycyclic aromatic hydrocarbon exposure and breast cancer incidence. Int J Cancer 2016; 139:310-21. [PMID: 26946191 DOI: 10.1002/ijc.30079] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 01/07/2016] [Accepted: 02/04/2016] [Indexed: 12/24/2022]
Abstract
Vehicular traffic polycyclic aromatic hydrocarbons (PAHs) have been associated with breast cancer incidence in epidemiologic studies, including our own. Because PAHs damage DNA by forming adducts and oxidative lesions, genetic polymorphisms that alter DNA repair capacity may modify associations between PAH-related exposures and breast cancer risk. Our goal was to examine the association between vehicular traffic exposure and breast cancer incidence within strata of a panel of nine biologically plausible nucleotide excision repair (NER) and base excision repair (BER) genotypes. Residential histories of 1,508 cases and 1,556 controls were assessed in the Long Island Breast Cancer Study Project between 1996 and 1997 and used to reconstruct residential traffic exposures to benzo[a]pyrene, as a proxy for traffic-related PAHs. Likelihood ratio tests from adjusted unconditional logistic regression models were used to assess multiplicative interactions. A gene-traffic interaction was evident (p = 0.04) for ERCC2 (Lys751); when comparing the upper and lower tertiles of 1995 traffic exposure estimates, the odds ratio (95% confidence interval) was 2.09 (1.13, 3.90) among women with homozygous variant alleles. Corresponding odds ratios for 1960-1990 traffic were also elevated nearly 2-3-fold for XRCC1(Arg194Trp), XRCC1(Arg399Gln) and OGG1(Ser326Cys), but formal multiplicative interaction was not evident. When DNA repair variants for ERCC2, XRCC1 and OGG1 were combined, among women with 4-6 variants, the odds ratios were 2.32 (1.22, 4.49) for 1995 traffic and 2.96 (1.06, 8.21) for 1960-1990 traffic. Our study is first to report positive associations between traffic-related PAH exposure and breast cancer incidence among women with select biologically plausible DNA repair genotypes.
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Affiliation(s)
| | - Jan Beyea
- Consulting in the Public Interest, Lambertville, NJ
| | - Amy H Herring
- Biostatistics, University of North Carolina, Chapel Hill, NC.,Carolina Population Center, University of North Carolina, Chapel Hill, NC
| | - Maureen Hatch
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | | | - Susan L Teitelbaum
- Department of Preventive Medicine, Mount Sinai School of Medicine, New York, NY
| | | | | | | | | | - Susan E Steck
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, South Carolina, CA
| | - Alfred I Neugut
- Department of Epidemiology, Columbia University, New York, NY.,Departments of Medicine, Columbia University, New York, NY
| | - Pavel Rossner
- Environmental Health Sciences, Columbia University, New York, NY.,Laboratory of Genetic Ecotoxicology, Institute of Experimental Medicine as CR, Prague, Czech Republic
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Tulbah S, Alabdulkarim H, Alanazi M, Parine NR, Shaik J, Pathan AAK, Al-Amri A, Khan W, Warsy A. Polymorphisms in RAD51 and their relation with breast cancer in Saudi females. Onco Targets Ther 2016; 9:269-77. [PMID: 26834486 PMCID: PMC4716748 DOI: 10.2147/ott.s93343] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The present study aimed at investigating the relationship between rs1801320 (G>C), rs1801321 (G>T), and rs2619681 (C>T) RAD51 gene polymorphisms and the risk of breast cancer development in Saudi females. The genotypes were analyzed using TaqMan genotyping assay and polymerase chain reaction-restriction fragment length polymorphism. The genotype and allele frequencies were computed using chi-square or Fisher’s exact test (two-tailed) by SPSS 21 software. The results showed that rs1801321G>T GG genotype and G allele frequency were strongly (P<0.0001) related to an elevated risk of breast cancer, while the mutant T allele appeared to provide protection against breast cancer development as observed from the significantly lower (P<0.0001) frequencies of the TT and GT genotypes in cancer patients compared to the healthy controls. The variant rs1801320G>C showed no significant differences in the frequencies of the genotypes and alleles in the patients and the control groups. The CC genotype and C allele frequency of rs2619681 (C>T) variant were significantly (P=0.012) higher in cancer patients, whereas the T allele showed a protective effect against cancer development. The frequencies of the three single-nucleotide polymorphisms did not differ in cancer patients with different tumor grades and human epidermal growth factor receptor 2 status (+ or −). However, the genotype frequency of rs1801320 (135G>C) differed in the patients with estrogen receptor (ER)+ and ER−, where CC genotype showed a significantly higher prevalence in the females with ER− who were suffering from breast cancer. In addition, the frequency of C allele of rs2619681 (C>T) was also significantly higher in the breast cancer patients who were ER+ and progesterone receptor (PR)+ compared to those with ER− and PR−. In the Saudi females, rs1801320 did not show an association with risk of breast cancer. Taken together, the results suggest that RAD51 rs1801321 polymorphism may be involved in the etiology of breast cancer in the Saudi females; however, further studies are necessary to confirm this relation.
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Affiliation(s)
- Sahar Tulbah
- Department of Biochemistry, College of Science, King Saud University, Center of Scientific and Medical Colleges, Riyadh, Saudi Arabia
| | - Huda Alabdulkarim
- Department of Hematology/Oncology, King Fahad Medical City Hospital, Comprehensive Cancer Center, King Saud University, Riyadh, Saudi Arabia
| | - Mohammad Alanazi
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Narasimha Reddy Parine
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Jilani Shaik
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Akbar Ali Khan Pathan
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Abdullah Al-Amri
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Wajahatullah Khan
- Basic Sciences Department, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Arjumand Warsy
- Department of Biochemistry, College of Science, King Saud University, Center of Scientific and Medical Colleges, Riyadh, Saudi Arabia
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Wang F, Zhao Q, He HR, Zhai YJ, Lu J, Hu HB, Zhou JS, Yang YH, Li YJ. The association between XRCC1 Arg399Gln polymorphism and risk of leukemia in different populations: a meta-analysis of case-control studies. Onco Targets Ther 2015; 8:3277-87. [PMID: 26609240 PMCID: PMC4644162 DOI: 10.2147/ott.s92752] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Background Associations between Arg399Gln single-nucleotide polymorphism (SNP) in the XRCC1 gene and leukemia susceptibility have been studied extensively, however, the results are inconsistent. The aim of this study was to determine these associations using meta-analytical methods. Methods A meta-analysis was performed to examine the associations between XRCC1 Arg399-Gln SNP and leukemia risk. A literature search of PubMed and Web of Science databases was conducted to identify relevant studies published up to March 10, 2015. The references of the retrieved articles were also screened. All the statistical analyses were conducted using Review Manager software. Results The XRCC1 Arg399Gln SNP was found to be associated with increased childhood risk of acute lymphoblastic leukemia among Asians under the dominant (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.50–2.97, P<0.0001), allele contrast (OR 1.72, 95% CI 1.33–2.23, P<0.0001), and homozygote contrast (OR 2.34, 95% CI 1.25–4.36, P=0.008) models. However, no association was found in Caucasians between the SNP and risk of either chronic myeloid leukemia or chronic lymphocytic leukemia under any contrast model. Conclusion The findings of the current meta-analysis indicate that the XRCC1 Arg399Gln SNP is a risk factor for childhood lymphoblastic leukemia in Asians.
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Affiliation(s)
- Fang Wang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Centre, Xi'an, People's Republic of China ; College of Pharmacy, Xi'an Medical University, Xi'an, People's Republic of China
| | - Qian Zhao
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Centre, Xi'an, People's Republic of China ; College of Pharmacy, Xi'an Medical University, Xi'an, People's Republic of China
| | - Hai-Rong He
- Clinical Research Center, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Ya-Jing Zhai
- Department of Pharmacy, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Jun Lu
- Clinical Research Center, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Hai-Bo Hu
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Centre, Xi'an, People's Republic of China
| | - Jin-Song Zhou
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Centre, Xi'an, People's Republic of China
| | - Yong-Hua Yang
- Department of Pediatrics, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Yuan-Jie Li
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Centre, Xi'an, People's Republic of China
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Zhang X, Li J, He Z, Duan H, Gao W, Wang H, Yu S, Chen W, Zheng Y. Associations between DNA methylation in DNA damage response-related genes and cytokinesis-block micronucleus cytome index in diesel engine exhaust-exposed workers. Arch Toxicol 2015; 90:1997-2008. [DOI: 10.1007/s00204-015-1598-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 09/10/2015] [Indexed: 01/07/2023]
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Jing JJ, Sun LP, Xu Q, Yuan Y. Effect of ERCC8 tagSNPs and their association with H. pylori infection, smoking, and alcohol consumption on gastric cancer and atrophic gastritis risk. Tumour Biol 2015; 36:9525-35. [PMID: 26130415 DOI: 10.1007/s13277-015-3703-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 06/22/2015] [Indexed: 12/14/2022] Open
Abstract
Excision repair cross-complementing group 8 (ERCC8) plays a critical role in DNA repair. Genetic polymorphisms in ERCC8 may contribute to the risk of cancer development. We selected tag single nucleotide polymorphisms (tagSNPs) in Chinese patients from the HapMap database to investigate associations with gastric cancer and its precursors. Genomic DNA was extracted from 394 controls, 394 atrophic gastritis, and 394 gastric cancer cases in northern Chinese patients, and genotypes were identified using the Sequenom MassARRAY system. We found that the ERCC8 rs158572 GG+GA genotype showed a 1.651-fold (95 % confidence interval (CI) = 1.109-2.457, P = 0.013) increased risk of gastric cancer compared with the AA genotype, especially in diffuse type. Stratified analysis comparing the common genotype revealed significantly increased gastric cancer risk in males and individuals older than 50 years with rs158572 GA/GG/GG+GA genotypes, while individuals older than 50 years with rs158916 CT/CC+CT genotypes were less susceptible to atrophic gastritis. Haplotype analysis showed that the G-T haplotype was associated with increased risk of gastric cancer. Statistically significant interactions between the two ERCC8 tagSNPs and Helicobacter pylori infection were observed for gastric cancer and atrophic gastritis risk (P < 0.05). Smokers and drinkers with ERCC8 rs158572 GG+GA genotype were more susceptible to gastric cancer compared with non-smokers and non-drinkers homozygous for AA. Our findings suggested that ERCC8 rs158572 and rs158916, alone or together with environmental factors, might be associated with gastric cancer and atrophic gastritis susceptibility. Further validation of our results in larger populations along with additional studies evaluating the underlying molecular function is required.
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Affiliation(s)
- Jing-Jing Jing
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Heping District, Nanjing North Street 155#, Shenyang City, 110001, China.,Key Laboratory of Cancer Etiology and Prevention, Liaoning Provincial Education Department, China Medical University, Shenyang, 110001, China
| | - Li-Ping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Heping District, Nanjing North Street 155#, Shenyang City, 110001, China.,Key Laboratory of Cancer Etiology and Prevention, Liaoning Provincial Education Department, China Medical University, Shenyang, 110001, China
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Heping District, Nanjing North Street 155#, Shenyang City, 110001, China.,Key Laboratory of Cancer Etiology and Prevention, Liaoning Provincial Education Department, China Medical University, Shenyang, 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Heping District, Nanjing North Street 155#, Shenyang City, 110001, China. .,Key Laboratory of Cancer Etiology and Prevention, Liaoning Provincial Education Department, China Medical University, Shenyang, 110001, China.
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48
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Jin G, Wang M, Chen W, Shi W, Yin J, Gang W. Single nucleotide polymorphisms of nucleotide excision repair and homologous recombination repair pathways and their role in the risk of osteosarcoma. Pak J Med Sci 2015; 31:269-73. [PMID: 26101473 PMCID: PMC4476324 DOI: 10.12669/pjms.312.6569] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Revised: 01/06/2015] [Accepted: 01/18/2015] [Indexed: 12/16/2022] Open
Abstract
Objective: To evaluate the influence of polymorphisms in nucleotide excision repair (NER) and homologous recombination repair (HRR) pathways on the development of osteosarcoma patients. Methods: Genotypes of ERCC1 rs11615 and rs3212986, ERCC2 rs1799793 and rs13181, NBN rs709816 and rs1805794, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539 were conducted by Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) assay. Results: Total 148 osteosarcoma patients and 296 control subjects were collected from Taizhou First People’s Hospital. Conditional logistic regression analyses found that individuals carrying with GA+AA genotype of ERCC2 rs1799793 and GC+CC genotype of NBN rs1805794 were significantly associated with increased risk of osteosarcoma, and the ORs(95%CI) were 1.58(1.03-2.41) and 2.66(1.73-4.08), respectively. We found that GA+AA genotype of ERCC2 rs1799793 or GC+CC genotype of NBN rs1805794 were associated with an increased risk of osteosarcoma in females, with ORs(95%CI) of 2.42(1.20-4.87) and 2.01(1.07-4.23), respectively. Conclusion: Our results suggest that ERCC2 rs1799793 and NBN rs1805794 polymorphisms were associated with an increased risk for osteosarcoma, which suggests that NER and HRR pathways modulate the risk of developing osteosarcoma.
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Affiliation(s)
- Guojun Jin
- Guojun Jin, Department of Hand and foot Surgery, Taizhou First People's Hospital, Taizhou, China
| | - Min Wang
- Min Wang, Department of Orthopedics, Taizhou First People's Hospital, Taizhou, China
| | - Weida Chen
- Weida Chen, Department of Hand and foot Surgery, Taizhou First People's Hospital, Taizhou, China
| | - Wei Shi
- Wei Shi, Department of Hand and foot Surgery, Taizhou First People's Hospital, Taizhou, China
| | - Jiapeng Yin
- Jiapeng Yin, Department of Burns and Plastic Surgery, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Wang Gang
- Wang Gang, Department of Hand and foot Surgery, Taizhou First People's Hospital, Taizhou, China
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49
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Quantification of DNA repair capacity towards oxidatively damaged DNA in subcellular and cellular systems by a nonradioactive cleavage assay. Methods Mol Biol 2015; 1208:73-84. [PMID: 25323500 DOI: 10.1007/978-1-4939-1441-8_6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
The identification of appropriate biomarkers for oxidative stress is one major aim in molecular epidemiology. Besides the quantification of specific DNA lesions such as of 8-oxoguanine (8oxoG), another approach consists in the assessment of the repair capacity towards 8oxoG, mediated predominantly by the human 8-oxoguanine DNA glycosylase 1 (hOGG1); further processing of base excision repair involves AP endonuclease 1 (APE1). Thus, during the last few years the so-called cleavage assays have been described, investigating the incision capacity of cell extracts towards (32)P-labelled and 8oxoG damaged oligonucleotides. Here, we describe a sensitive nonradioactive test system based on Cy5-labelled oligonucleotides with hairpin-like structures, enabling the assessment of activities of the isolated hOGG1 and APE1 as well as their activities in extracts prepared from cultured cells or peripheral blood mononuclear cells (PBMC). This approach allows the sensitive quantification of modulating exposures, such as inhibitory metal compounds, and also the determination of interindividual differences in DNA repair capacities. The method is as sensitive and even faster as compared to the use of radioactively labelled oligonucleotides and additionally offers the advantage of reduced costs and low health risk.
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50
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Gómez M, Guillem V, Pereira A, Ferrer-Marín F, Álvarez-Larrán A, Kerguelen A, Estrada N, Martínez-López J, Angona A, Amat P, Navarro B, Besses C, Hernández-Boluda JC. Risk factors for non-melanoma skin cancer in patients with essential thrombocythemia and polycythemia vera. Eur J Haematol 2015; 96:285-90. [DOI: 10.1111/ejh.12588] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2015] [Indexed: 12/20/2022]
Affiliation(s)
- Montse Gómez
- Hematology and Medical Oncology Department; Hospital Clínico Universitario; INCLIVA; Valencia Spain
| | - Vicent Guillem
- Hematology and Medical Oncology Department; Hospital Clínico Universitario; INCLIVA; Valencia Spain
| | - Arturo Pereira
- Hemotherapy and Hemostasis Department; Hospital Clínic; Barcelona Spain
| | | | | | - Ana Kerguelen
- Hematology Department; Hospital La Paz; Madrid Spain
| | - Natàlia Estrada
- Hematology Department; Institut Català d'Oncologia-Hospital Germans Trias i Pujol; Badalona Spain
| | | | - Anna Angona
- Hematology Department; Hospital del Mar-IMIM; Barcelona Spain
| | - Paula Amat
- Hematology and Medical Oncology Department; Hospital Clínico Universitario; INCLIVA; Valencia Spain
| | - Blanca Navarro
- Hematology and Medical Oncology Department; Hospital Clínico Universitario; INCLIVA; Valencia Spain
| | - Carles Besses
- Hematology Department; Hospital del Mar-IMIM; Barcelona Spain
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