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

Abstract

BackgroundGenetic 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.MethodsWe 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 Arg194Trp, Arg280His, Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln), 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.ResultsThe 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.ConclusionOur results suggest an increased risk for advanced colorectal neoplasia in individuals with the XRCC1 Arg280His polymorphism and a reduced risk associated with the XRCC1 Arg399Gln polymorphism. Interestingly, individuals with the XPD Lys751Gln polymorphism had an increased risk of low-risk adenomas. This may suggest a role in regression of adenomas.

XRCC3 Thr241Met Gene Polymorphism and Risk of Colorectal Cancer in Kashmir: a Case Control Study

“…(95% CI=0.96-5.4). Our findings are in concordance with those reported by Mort et al (2003), Krupa et al (2011) andImporta et al (2008) and contradictory to those reported by many authors (Tranah et al, 2004;Stern et al, 2005;Yeh et al, 2005;Skjelbred et al, 2006) which show negative association. Also, it has been suggested that variant genotypes of XRCC3 have decreased repair capacity and thus individuals with this genotypes do not repair double strand DNA breaks efficiently by HRR and are susceptible to risk of CRC (Krupa et al, 2011).…”

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual’s susceptibility to sporadic colorectal cancer

“…For example, the results of the study of Skjelbred CF et al studies on Norwegian cohort suggested that XPD A18911C (Lys751Gln) variant is associated with an increased risk of low-risk adenomas, but not carcinomas [15], while Hansen's RD et al studies on 160,725 Danish individuals revealed that the XPD A18911C (Lys751Gln) variant is not of a major importance in colorectal carcinogenesis [22]. Results similar to those of Hansen et al [22] were recently published by ref.…”

“…The 194Trp variant has also been found to be protective against lung cancer, although it is associated with an increased risk of CRC [8]. The results for the Arg399Gln polymorphism of the XRCC1 gene in colorectal cancer epidemiology are very ambiguous [13][14][15][16][17][18].…”

Aspirin and alterations in DNA repair proteins in the SW480 colorectal cancer cell line

“…XRCC3 deficient HCT116 cells have shown increased sensitivity to cisplatin and mitomycin C (42). Although some studies have shown no association between polymorphisms in XRCC3 and colorectal cancer risk (43)(44)(45)(46) other studies have (47,48), and in addition XRCC3 polymorphisms have also been associated with breast and lung cancer susceptibility (41,49).…”