Polymorphisms of the XRCC1, XRCC3 and XPD genes and risk of colorectal adenoma and carcinoma, in a Norwegian cohort: a case control study (original) (raw)
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Journal of Cancer Research and Clinical Oncology, 2010
Purpose Genetic polymorphisms in DNA repair genes may inXuence variations in individual DNA repair capacity, which could be associated with the development of cancer. We detected the distributions of three single-nucleotide polymorphisms (XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln) in DNA repair genes, and assessed the associations of these genetic polymorphisms with colon and rectal cancer susceptibility as well as evaluated the interactions of gene-gene and gene-environment in a casecontrol study of an Indian population. Methods This case-control study was conducted with 302 cases (including 59 colon and 243 rectal cancer patients) and 291 cancer-free healthy controls. Genotypes were determined by PCR-RLFP assays. The eVects [odds ratios (ORs) and 95% conWdence intervals (95% CIs)] of genetic polymorphisms on colorectal cancer were estimated using unconditional logistic regression. Results The XRCC1 399Gln allele was found to be associated with a signiWcantly increased rectal cancer risk among men (OR = 1.65, 95% CI 1.04-2.64). Whereas the XRCC3 241Met allele showed a protective tendency against rectal cancer (OR = 0.68, 95% CI 0.46-1.02) for both men and women. Furthermore, a combination of the XRCC1 399Gln allele with XRCC3 Thr/Thr genotype and the XPD 751Gln allele demonstrated the highest rectal cancer risk (OR = 3.52, 95% CI 1.43-9.44). Conclusions The combined eVects of putative risk alleles/ genotypes for diVerent DNA repair pathways may strengthen the susceptibility to rectal cancer.
Cytology and Genetics, 2020
Although the specific causes of colorectal cancer (CRC) are not known, a robust DNA repair capacity may decrease the risk of this malignancy. DNA repair capacity may be reduced by alterations of genes involved in DNA repair process. This may affect susceptibility to carcinogenesis. It is hypothesized that single nucleotide polymorphisms (SNPs) of several DNA repair genes may be a risk factor for CRC susceptibility and prognosis. Using PCR-RFLP method, we conducted a case-control study to genotype 291 patients with CRC and 140 healthy individuals to determine variants in the PRKDC, XPD and XRCC1 genes. Results showed that the genotypes of XRCC1 c.580C>T polymorphism were associated with the risk of CRC. Compared with CC, CT (odds ratio (OR) = 5.35, P < 0.001) and CT/TT (OR = 4.74, P < 0.001) as well as T allele (OR = 4.95, P < 0.001) were overrepresented among the CRC patients. Variant genotype CC (OR = 2.37; P = 0.042) and C allele of XPD c.2251A>C (OR = 1.37; P = 0.028) polymorphism, enhanced the risk of CRC cases. Compared with GG, positive association was also obtained for all genotypes (GT, TT, GT/TT) of PRKDC rs7003908; 6721G>T polymorphism with CRC. Moreover, T allele of PRKDC demonstrated significant risk for CRC (OR = 5.61; P < 0.001). Besides, significant relevance of the PRKDC rs7003908; 6721G>T variations to smoking as well as XPD c.2251A>C variations to smoking and alcohol consumption in individuals with CRC was observed. Our findings indicated that genetic polymorphisms of PRKDC, XRCC1, XPD genes may influence susceptibility of CRC in the Iranian population.
Cancer Epidemiology Biomarkers & Prevention, 2006
Objectives: Nucleotide excision repair enzymes remove bulky damage caused by environmental agents, including carcinogenic polycyclic aromatic hydrocarbons found in cigarette smoke, a risk factor for colorectal adenoma. Among participants randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we studied the risk of advanced colorectal adenoma in relation to cigarette smoking and selected single nucleotide polymorphisms (SNP) in the nucleotide excision repair pathway. Methods: Cases (n = 772) were subjects with left-sided advanced adenoma (>1 cm in size, high-grade dysplasia, or villous characteristics). Controls (n = 777) were screennegative for left-sided polyps by sigmoidoscopy. DNA was extracted from blood samples and 15 common nonsynonymous SNPs in seven-nucleotide excision repair genes [XPC, RAD23B (hHR23B), CSB (ERCC6), XPD (ERCC2), CCNH, XPF (ERCC4), and XPG (ERCC5)] were genotyped. Results: None of the studied SNPs were independently associated with advanced adenoma risk. Smoking was related to adenoma risk and XPC polymorphisms (R 492 H , A 499 V , K 939 Q) modified these effects (P interaction from 0.03-0.003). Although the three XPC variants were in linkage disequilibrium, a multivariate logistic regression tended to show independent protective effects for XPC 499 V (P trend = 0.06), a finding supported by haplotype analysis (covariateadjusted global permutation P = 0.03). Conclusions: Examining a spectrum of polymorphic variants in nucleotide excision repair genes, we found evidence that smoking-associated risks for advanced colorectal adenoma are modified by polymorphisms in XPC, particularly haplotypes containing XPC 499 V. (Cancer Epidemiol Biomarkers Prev 2006;15(2):306-11)
Clinical Cancer Research, 2006
Objectives: We have undertaken a comprehensive study of common polymorphisms in genes of DNA repair, exploring both the risk of developing colorectal cancer and the prognosis of patients. Methods: Subjects from a case-control study (377 cases and 329 controls) designed to assess gene-environment interactions were genotyped by use of an oligonucleotide microarray and the arrayed primer extension technique. Twenty-eight single nucleotide polymorphisms in 15 DNA repair genes were included. The candidate genes belong to different DNA repair pathways: base excision repair (OGG1, LIG3, APEX, POLB, XRCC1, PCNA, and MUTYH), nucleotide excision repair (ERCC1, ERCC2, ERCC4, and ERCC5), double-strand breaks repair (XRCC2, XRCC3, and XRCC9), and reversion repair (MGMT) genes. Results: Polymorphism OGG1 S326C was associated with an increased risk of colorectal cancer [odds ratio (OR), 2.3; 95% confidence interval (95% CI), 1.1-5.0], the risk being higher in younger individuals. A haplotype of ERCC1 was associated with increased risk (OR, 2.3; 95% CI, 1.0-5.3). POLB P242R was also associated with decreased risk (OR, 0.23; 95% CI, 0.05-0.99), although the number of variant allele carriers was low. In the univariate analysis, adjusted for age, sex, and Dukes' stage, three polymorphisms were significantly associated with better prognosis: XRCC1 R399Q [hazard ratio (HR), 0.38; 95% CI, 0.17-0.85], XRCC3 T141M (HR, 0.66; 95% CI, 0.45-0.97), and MGMT L84F (HR, 0.14; 95% CI, 0.02-0.99). ERCC1 19007T>C was associated with worse prognosis (HR, 1.51; 95% CI, 1.01-2.27). In a multivariate analysis, only XRCC1 R399Q and ERCC1 19007T>C remained significant. These associations were stronger among patients receiving adjuvant chemotherapy. Conclusions: Although the overall effect of DNA repair genes in colorectal cancer etiology seems limited, their influence in the response to chemotherapy and prognosis may be more relevant. This knowledge may help to clarify the utility of specific adjuvant treatments according to the individual genetic background.
DNA repair genes polymorphisms and risk of colorectal cancer in Saudi patients
Arab Journal of Gastroenterology, 2016
Background and study aims: Polymorphisms in the DNA repair genes may influence individual capacity to repair DNA damage, which may be associated with increased genetic instability and carcinogenesis. Our aim was to evaluate the relation of genetic polymorphisms in 2 DNA repair genes, XPD Lys751Gln and XRCC1 (A399G), with colorectal cancer (CRC) susceptibility. We further investigated the potential effect of these DNA repair variants on clinicopathological parameters of CRC patients. Patients and methods: Both XPD and XRCC1 polymorphisms were characterised in one hundred CRC patients and one hundred healthy controls who had no history of any malignancy by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method and PCR with confronting twopair primers (PCR-CTPP), using DNA from peripheral blood in a case control study. Results: Our results revealed that the frequencies of GG genotype of XRCC1 399 polymorphism were significantly higher in the CRC patients than in the normal individuals (p 6 0.03), and did not observe any association between the XPD Lys751Gln polymorphism and CRC risk. We found association between both XRCC1 A399G polymorphisms and histological grading of disease. Conclusion: Our results suggested that, XRCC1 gene is an important candidate gene for susceptibility to colorectal carcinoma.
The genes RAD51 and XRCC2 encode proteins that are important for the repair of double-strand DNA breaks by recombination. Therefore, genetic variability in these genes may contribute to the occurrence and progression of carcinoma. We investigated the association of polymorphisms in the DNA repair genes XRCC2-A/G and RAD51-135G/C with the colorectal cancer risk. Genotypes were determined by PCR-RFLP assays in 71 patients with colorectal cancer and 86 age-matched healthy controls. After amplification, we used a restriction enzyme (RAD51; MvaI and XRCC2; HphI) and digested the PCR product. Then, this DNA fragments were passed through gel electrophoresis. By examining these images, we identified changes in the nucleotides in these specific regions. To clarify fragments polymorphisms, the PCR products were sequenced with an Applied Biosystems Automated Sequencer. We observed the Arg188His polymorphism of XRCC2 genes in 42.2%, as shown in 30 of the 71 cancer patients. Only 21 out of 86 controls showed this polymorphism (24.2%). We also observed that 21 of the 71 patients (29.5%) carried the RAD51135G/C polymorphism of this gene. The same polymorphism was observed in 11 of the 86 controls (12.7 %; p < 0.05). The obtained results indicate that the polymorphism of RAD51 and XRCC2 genes may be associated with the incidence of colon cancer in the Turkish population. Further studies, including those on a larger group of patients, are required to further clarify this point. Figure 2. XRCC2 gene sequencing results. A. In control subjects the SNP region is shown as normal (TT). B and C. Sequence results for SNP site difference (GT) in colon cancer patients.
International journal of clinical and experimental medicine, 2015
The genes RAD51 and XRCC2 encode proteins that are important for the repair of double-strand DNA breaks by recombination. Therefore, genetic variability in these genes may contribute to the occurrence and progression of carcinoma. We investigated the association of polymorphisms in the DNA repair genes XRCC2-A/G and RAD51-135G/C with the colorectal cancer risk. Genotypes were determined by PCR-RFLP assays in 71 patients with colorectal cancer and 86 age-matched healthy controls. After amplification, we used a restriction enzyme (RAD51; MvaI and XRCC2; HphI) and digested the PCR product. Then, this DNA fragments were passed through gel electrophoresis. By examining these images, we identified changes in the nucleotides in these specific regions. To clarify fragments polymorphisms, the PCR products were sequenced with an Applied Biosystems Automated Sequencer. We observed the Arg188His polymorphism of XRCC2 genes in 42.2%, as shown in 30 of the 71 cancer patients. Only 21 out of 86 co...
Asian Pacific journal of cancer prevention : APJCP, 2015
Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of developing cancer. For colorectal cancer the importance of mutations in mismatch repair genes has been extensively documented. In this study we focused on the Arg194Trp polymorphism of the DNA repair gene XRCC1, involved in base excision repair (BER) and its role in colorectal cancer in Kashmiri population. A case-control study was conducted including 100 cases of colorectal cancer, and 100 hospital-based age- and sex-matched healthy controls to examine the role of XRCC1 genetic polymorphisms in the context of colorectal cancer risk for the Kashmiri population. Genotype analysis of XRCC1 Arg194Trp was conducted with a restriction fragment length polymorphism (RFLP) method. The overall association between the XRCC1 polymorphism and the CRC cases was found to be significant (p<0.05) with both the heterozygous genotype (Arg/Trp) as well as homozyg...
DNA repair genetic polymorphisms and risk of colorectal cancer in the Czech Republic
Mutation research, 2008
Colorectal cancer represents a complex disease where susceptibility may be influenced by genetic polymorphisms in the DNA repair system. In the present study we investigated the role of nine single nucleotide polymorphisms in eight DNA repair genes on the risk of colorectal cancer in a hospital-based case-control population (532 cases and 532 sex- and age-matched controls). Data analysis showed that the variant allele homozygotes for the Asn148Glu polymorphism in the APE1 gene were at a statistically non-significant increased risk of colorectal cancer. The risk was more pronounced for colon cancer (odds ratio, OR: 1.50; 95% confidence interval, CI: 1.01-2.22; p=0.05). The data stratification showed increased risk of colorectal cancer in the age group 64-86 years in both individuals heterozygous (OR: 1.79; 95% CI: 1.04-3.07; p=0.04) and homozygous (OR: 2.57; 95% CI: 1.30-5.06; p=0.007) for the variant allele of the APE1 Asn148Glu polymorphism. Smokers homozygous for the variant allel...
Molecular Biology Reports, 2011
XRCC2 and XRCC3 proteins are structurally and functionally related to RAD51 which play an important role in the homologous recombination, the process frequently involved in cancer transformation. In our previous work we show that the 135G[C polymorphism (rs1801320) of the RAD51 gene can modify the effect of the Thr241Met polymorphism (rs861539) of the XRCC3 gene. We tested the association between the 135G[C polymorphism of the RAD51 gene, the Thr241Met polymorphism of the XRCC3 gene and the Arg188His polymorphism (rs3218536) of the XRCC2 gene and colorectal cancer risk and clinicopathological parameters. Polymorphisms were evaluated by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) in 100 patients with invasive adenocarcinoma of the colon and in 100 sex, age and ethnicity matched cancer-free controls. We stratified the patients by genotypes, tumour Duke's and TNM stage and calculated the linkage of each genotype with each stratum. Carriers of Arg188Arg/Me241tMet, His188His/Thr241Thr and His 188His/G135G genotypes had an increased risk of colorectal cancer occurrence (OR 5.70, 95% CI 1.10-29.5; OR 12.4, 95% CI 1.63-94.9; OR 5.88, 95% CI 1.21-28.5, respectively). The C135C genotype decreased the risk of colorectal cancer singly (OR 0.06, 95% CI 0.02-0.22) as well as in combination with other two polymorphisms. TNM and Duke's staging were not related to any of these polymorphisms. Our results suggest that the 135G[C polymorphism of the RAD51 gene can be an independent marker of colorectal cancer risk. The Thr241Met polymorphism of the XRCC3 gene and the Arg188His polymorphism of the XRCC2 gene can modify the risk of colorectal cancer.