Polymorphisms of the XRCC1, XRCC3 and XPD genes and risk of colorectal adenoma and carcinoma, in a Norwegian cohort: a case control study

BACKGROUND: 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. Less is known about other DNA repair pathways in colorectal carcinogenesis. In this study we have focused on the XRCC1, XRCC3 and XPD genes, involved in base excision repair, homologous recombinational repair and nucleotide excision repair, respectively. METHODS: We used a case-control study design (157 carcinomas, 983 adenomas and 399 controls) to test the association between five polymorphisms in these DNA repair genes (XRCC1 Arg(194)Trp, Arg(280)His, Arg(399)Gln, XRCC3 Thr(241)Met and XPD Lys(751)Gln), and risk of colorectal adenomas and carcinomas in a Norwegian cohort. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression model adjusting for age, gender, cigarette smoking and alcohol consumption. RESULTS: The XRCC1 280His allele was associated with an increased risk of adenomas (OR 2.30, 95% CI 1.19–4.46). The XRCC1 399Gln allele was associated with a reduction of risk of high-risk adenomas (OR 0.62, 95% CI 0.41–0.96). Carriers of the variant XPD 751Gln allele had an increased risk of low-risk adenomas (OR 1.40, 95% CI 1.03–1.89), while no association was found with risk of carcinomas. CONCLUSION: Our results suggest an increased risk for advanced colorectal neoplasia in individuals with the XRCC1 Arg(280)His polymorphism and a reduced risk associated with the XRCC1 Arg(399)Gln polymorphism. Interestingly, individuals with the XPD Lys(751)Gln polymorphism had an increased risk of low-risk adenomas. This may suggest a role in regression of adenomas

Multiple Pathway-Based Genetic Variations Associated with Tobacco Related Multiple Primary Neoplasms

BACKGROUND: In order to elucidate a combination of genetic alterations that drive tobacco carcinogenesis we have explored a unique model system and analytical method for an unbiased qualitative and quantitative assessment of gene-gene and gene-environment interactions. The objective of this case control study was to assess genetic predisposition in a biologically enriched clinical model system of tobacco related cancers (TRC), occurring as Multiple Primary Neoplasms (MPN). METHODS: Genotyping of 21 candidate Single Nucleotide Polymorphisms (SNP) from major metabolic pathways was performed in a cohort of 151 MPN cases and 210 cancer-free controls. Statistical analysis using logistic regression and Multifactor Dimensionality Reduction (MDR) analysis was performed for studying higher order interactions among various SNPs and tobacco habit. RESULTS: Increased risk association was observed for patients with at least one TRC in the upper aero digestive tract (UADT) for variations in SULT1A1 Arg²¹³His, mEH Tyr¹¹³His, hOGG1 Ser³²⁶Cys, XRCC1 Arg²⁸⁰His and BRCA2 Asn³⁷²His. Gene-environment interactions were assessed using MDR analysis. The overall best model by MDR was tobacco habit/p53(Arg/Arg)/XRCC1(Arg³⁹⁹His)/mEH(Tyr¹¹³His) that had highest Cross Validation Consistency (8.3) and test accuracy (0.69). This model also showed significant association using logistic regression analysis. CONCLUSION: This is the first Indian study on a multipathway based approach to study genetic susceptibility to cancer in tobacco associated MPN. This approach could assist in planning additional studies for comprehensive understanding of tobacco carcinogenesis

Functional studies of accessory factors associated with base excision repair

Exposure to environmental and cellular mutagens is ubiquitous and, as a consequence, DNA is constantly faced with the possibility of becoming damaged. Base excision repair (BER) removes some of this damage to limit the impact of these exposures on cell physiology and ultimately human health. The function of core BER enzymes may be enhanced by other protein accessory factors, namely poly(ADP-ribose) polymerase-1 (PARP-1) and x-ray repair cross complementing gene 1 (XRCC1). The main hypothesis of this research was that genetic approaches using cellular knockout and complementation models can evaluate whether the accessory proteins PARP-1 and XRCC1 are determinants of BER efficiency. While numerous biochemical studies have implicated PARP-1 in BER, the role of this protein in BER is somewhat uncertain. The first aim of this research was to evaluate the role of PARP-1 in BER in vertebrate cells. Chicken cells lacking PARP-1 were treated with an alkylating agent under different scenarios with subsequent endpoint measurements. PARP-1 was necessary as a survival factor during chronic exposure but did not appear relevant in acute exposures until the late stages of BER. In the absence of exposure, the DNA lesions measured were equal between PARP-1 proficient and deficient cells. XRCC1 acts as a scaffold for numerous protein interactions necessary for proficient BER. However, the presence of polymorphic forms of XRCC1 in the human population may influence DNA repair and disease susceptibility. The second aim of this research was to demonstrate the applicability of using transgenic cells in a combined study design for determining the biological significance of XRCC1 polymorphisms. Isogenic, mammalian cells lacking XRCC1 were transfected with various forms of the human XRCC1 gene, exposed to different genotoxicants, and assessed for single strand break repair capacity. Only cells expressing the 280His variant showed a repair defect. Subsequently, evaluation of data from the Carolina Breast Cancer Study demonstrated associations between XRCC1 280His, smoking, and breast cancer. Together these studies demonstrate that accessory factors can influence BER efficiency and illustrate the importance of a multi-disciplinary approach for investigating the link between genes, the environment, and disease risk

XRCC1 and XPD genetic polymorphisms, smoking and breast cancer risk in a Finnish case-control study

INTRODUCTION: It has been suggested that individuals with reduced DNA repair capacities might have increased susceptibility to environmentally induced cancer. In this study, we evaluated if polymorphisms in DNA repair genes XRCC1 (Arg280His, Arg399Gln) and XPD (Lys751Gln) modify individual breast cancer risk, with emphasis on tobacco smoking. METHODS: The study population consisted of 483 incident breast cancer cases and 482 population controls of Finnish Caucasian origin. The genotypes were determined by PCR-RFLP-based methods. Odds ratio (OR) and confidence intervals (CIs) were calculated by unconditional logistic regression analyses. RESULTS: No statistically significant overall effect in the breast cancer risk was seen for any of the studied polymorphisms. However, a significant increase in breast cancer risk was seen among ever smoking women if they carried at least one XRCC1-399 Gln allele (OR 2.33, 95% CI 1.30–4.19, p(int )0.025) or XPD-751 Gln/Gln genotype (OR 2.52, 95% CI 1.27–5.03, p(int )0.011) compared to smoking women not carrying these genotypes. The risks were found to be confined to women smoking at least five pack-years; the respective ORs were 4.14 (95% CI 1.66–10.3) and 4.41 (95% CI 1.62–12.0). Moreover, a significant trend of increasing risk with increasing number of the putative at-risk genotypes (p for trend 0.042) was seen. Women with at least two at-risk genotypes had an OR of 1.54 (95% CI 1.00–2.41) compared to women with no at-risk genotypes. Even higher estimates were seen for ever actively smoking women with at least two at-risk genotypes. CONCLUSION: Our results do not indicate a major role for XRCC1 and XPD polymorphisms in breast cancer susceptibility, but suggest that they may modify the risk especially among smoking women

Assessment of role of genetic polymorphisms in XRCC1, XRCC2 and XRCC3 genes in cervical cancer susceptibility from a rural population: a hospital based case-control study from Maharashtra, India

Background: Cervical cancer is a major concern of health risk, moreover the leading cause of cancer causing deaths in women of rural parts of India. This study was aimed to assess the risk of cervical cancer development in association with polymorphisms in X-Ray Cross Complementing Group (XRCC1, XRCC2 and XRCC3) genes in the rural population of south-western Maharashtra. We focused to determine the frequency of polymorphisms in DNA repair genes including XRCC1 at codon (cd) 194, cd 280, cd 399, XRCC2 at cd 188 and XRCC3 at cd 241 and their plausible role in cervical cancer risk from rural parts of India.Methods: This study included 350 proven cases with cervical cancer and 400 age and sex matched controls. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to analyze the association XRCC1, XRCC2 and XRCC3 gene polymorphisms with cervical cancer development in women of South-Western Maharashtra.Results: The result from our study showed that allele frequencies of selected genes were not statistically different between the groups for XRCC1 Trp194, XRCC2 His188 and XRCC3 Met241. XRCC1 His280 (OR= 4.36; 95% CI= (3.20-5.95); p= <0.0001) and XRCC1 Gln399 (OR= 2.99; 95% CI= (1.60-5.56); p= <0.0001) genotypes significantly increased the risk of cervical cancer.Conclusions: This study indicates that polymorphisms in cd 280 of exon 9 and cd 399 of exon 10 of XRCC1 gene could play a role in modifying genetic susceptibility of individuals towards cervical cancer among women from rural Maharashtra. This case-control study suggest that selected DNA repair genes represent genetic determinants in cervical carcinogenesis along with other risk factors in the rural Indian population

Genetic epidemiology of breast cancer in CYPRUS: A case -control study of DNA repair genes

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.The occurrence of early-onset breast cancer (EOBC) has been associated with germline mutations in the BRCA1 and BRCA2 genes. The first aim of this thesis was to evaluate the frequency and distribution of mutations in these genes, in a group of Cypriot women diagnosed with EOBC. Pathogenic mutations were identified in 6 of the 26 unrelated patients. This study supports a strong correlation between the early onset breast cancer phenotype and the presence of pathogenic BRCA1/2 mutations. It is of interest that pathogenic mutations were detected in patients without a family history of the disease. Based on these results, we recommend that BRCA1/2 screening should be offered to patients with a diagnosis of EOBC irrespective of their family history. The known breast cancer susceptibility genes explain only about 5% of breast cancer cases. Thus, it is likely that other breast cancer susceptibility genes exist. The second aim of the present thesis was to assess whether alterations in DNA repair genes modify breast cancer risk in the Cypriot population. Towards this objective, blood samples were collected and genomic DNA isolated from 1109 Cypriot female breast cancer patients diagnosed between 40-70 years old, and from 1177 age-matched healthy female controls. A total of 79 single nucleotide polymorphisms (SNPs) were genotyped in all samples. Significant associations with breast cancer risk were observed for eight of the SNPs studied. Five SNPs in the BRCA2, MRE11A, MUS81, PBOV1 and XRCC1 genes, were associated with an increased risk for breast cancer, while two SNPs in the NBS1 gene and one SNP in the MRE11A gene appeared to be associated with reduced risk for the disease. The data from this study support the hypothesis that genetic variants in DNA repair genes influence breast cancer risk and provides further evidence for the existence of a polygenic model for breast cancer

Influência de polimorfismos em genes de reparação do DNA na frequência de anomalias cromossómicas radioinduzidas

Tese de mestrado, Biologia (Biologia Molecular e Genética), 2008, Universidade de Lisboa, Faculdade de CiênciasOs polimorfismos em genes que codificam proteínas envolvidas na reparação do DNA têm sido considerados como potencialmente modificadores do risco de cancro, particularmente em indivíduos expostos a agentes genotóxicos, tal como a radiação ionizante. Num estudo anterior, avaliou-se o nível de alterações citogenéticas e a competência de reparação das lesões no DNA, num grupo de residentes na vizinhança de minas de urânio e seus resíduos, comparativamente a dois grupos não expostos. As frequências de aberrações cromossómicas (ACs) estáveis e instáveis, quer espontâneas quer radioinduzidas in vitro em linfócitos, foram determinadas por hibridação in situ fluorescente. O presente estudo visou investigar a influência dos polimorfismos em genes de reparação do DNA envolvidos na reparação de danos radioinduzidos - hOGG1, XRCC1, XPD, XRCC3, RAD51 e NBS1 - nas frequências de ACs nos grupos referidos. A genotipagem foi efectuada pelo método de PCR-RFLP. Os resultados mostraram que não existe uma associação estatisticamente significativa entre qualquer dos polimorfismos genéticos estudados e a frequência espontânea de ACs, excepto para o alelo variante 751Gln de XPD. Contudo, detectaram-se algumas associações estatisticamente significativas entre determinados genótipos e a frequência de ACs radioinduzidas. Assim, verificou-se que tanto o alelo variante 194Trp de XRCC1 como o alelo 751Gln de XPD estão associados a uma redução significativa de ACs radioinduzidas. Ao invés, os alelos variantes 280His de XRCC1 e 135C de RAD51 estão, em geral, associados a um aumento significativo de ACs. Em conclusão, os resultados obtidos vêm confirmar a hipótese de que polimorfismos em genes de reparação do DNA afectam os níveis de aberrações cromossómicas radioinduzidas tendo, possivelmente, um efeito modulador do risco individual para o desenvolvimento de cancroPolymorphisms in DNA repair genes coding DNA repair proteins have been considered as potential modifiers of cancer risk, particularly in individuals exposed to genotoxic agents, such as ionizing radiation. In a previous study the level of cytogenetic damage and the DNA repair competence were evaluated in a group of individuals living in the vicinity of uranium mines and its residues (GE), in comparison with two non-exposed groups (GNE and GR). Data on the frequencies of spontaneous and gamma-rays induced stable and unstable chromosome aberrations (CA) in vitro in lymphocytes, were determined by fluorescent in situ hybridization. The aim of the present study was to investigate the influence of polymorphisms in DNA repair genes involved in the repair of ionizing radiation-induced DNA damage - hOGG1, XRCC1, XPD, XRCC3, RAD51 and NBS1 - on the frequencies of CA in referred groups. Genotyping was performed by PCR-RFLP method. We found is no statistically significant association between any genetics polymorphisms and the frequencies of spontaneous CA, except for XPD 751Gln variant allele. However, some statistically significant associations were observed between certain genotypes and the frequency of radiation-induced CA. In fact, it was observed that both XRCC1 194His and XPD 751Gln variant alleles are associated with a significant reduction of radio-induced CA. In contrast, XRCC1 280His and RAD51 135C variant alleles are, in general, associated with an significant increase of CA. In conclusion, our results support the hypothesis that polymorphisms in DNA repair genes affect radiation-induced chromosome aberration levels and possibly modulate individual cancer ris

Genetic Single Nucleotide Polymorphisms (GSNPs) in the DNA Repair Genes and Hepatocellular Carcinoma Related to Aflatoxin B1 among Guangxiese Population

Aflatoxin B1 (AFB1) is an important environmental carcinogen for the development of hepatocellular carcinoma (HCC). HCC is a complex disease likely resulting from genetic single nucleotide polymorphisms (GSNPs) of multiple interacting genes and gene-environment interactions. Recent efforts have been made to analyze the associations between risk of this malignancy and GSNPs in genes involved in the repair of DNA damage induced by AFB1. Here, we reviewed the results of published case-control studies that have examined the effects of common alleles of all susceptible DNA repair genes, including XRCC1, XRCC3, XRCC4, XRCC7, XPC, and XPD, on risk of AFB1-related HCC among Guangxi population. Statistically significant differences in genotype frequencies found in case-control comparisons were rs25487, rs80309960, rs861539, rs7003908, rs28383151, rs3734091, rs13181, and rs2228001 polymorphism. The overall effects of these GNSPs were moderate in terms of relative risk, with ORs ranging from 2 to 10. Furthermore, some evidence of the interaction of GSNPs in DNA repair genes and AFB1 exposure modulate risk of this cancer was also found, although the results require confirmation with larger sample size studies