| Summary: | 碩士 === 中山醫學大學 === 醫學分子毒理學研究所 === 95 === X-ray cross-complementing group 1 (XRCC1) is a base excision repair (BER) gene. There are 17 polymorphisms of XRCC1 been reported. Among these, the association of cancer risk of three polymorphisms of XRCC1 including 5’UTR T-77C, Exon 6 Arg194Trp and Exon 10 Arg399Gln has been extensively investigated. 5’UTR T-77C was association with increased lung cancer risk by reduced transcriptional activity of XRCC1. XRCC1 Arg194Trp and Arg399Gln could interact with some proteins involved in BER to decrease DNA repair activity. It has been shown that subjects with Arg/Trp + Trp/Trp at 194 codon had higher risk of lung cancer than those with Arg/Arg. However, no consistent result was obtained from previous reports regarding Arg399Gln polymorphism. Interestingly, subjects with Gln/Gln at 399 codon exhibited higher p53 mutation frequency than those with Arg/Arg genotype. Therefore, we will conduct a case-control study to understand whether the three genetic polymorphisms of XRCC1 were associated with lung cancer risk? Whether the lung cancer risk caused by these genetic polymorphisms was mediated through the increase of p53 mutation? Additionally, whether patient’s survival could be influenced by these genetic polymorphisms of XRCC1?
To answer those questions, 296 lung cancer cases and 288 non-cancer hospital controls were enrolled to determine the genotypes of XRCC1 by PCR-RFLP. Multiple logistic regression was performed to statistically analyzed understanding which genotype of XRCC1 was associated with lung cancer risk. The association of XRCC1 genotypes with patient’s survival was statistically analyzed by Kaplan-Meier method. Our data showed that male subjects with combination of TC + CC and Arg/Trp + Trp/Trp genotype had 3.51-fold lung cancer risk of those with the combination of TT and Arg/Trp + Trp/Trp genotype (95% CI = 1.028-11.961, p = 0.045). We also observed that female cases with Gln/Gln genotype exhibited a significantly higher p53 mutation frequency than those with Arg/Arg genotype (OR = 4.11, 95% CI = 1.050-16.117, p = 0.042). On the other hand, male cases with T/C + C/C genotype had more common to have p53 mutation than those with T/T genotype (OR = 1.99, 95% CI = 0.906-4.353, p = 0.087), but it did not reach statistically significant. Among the prognostic influence of XRCC1 polymorphisms, we only observed that patients with TC + CC genotype had longer survival time than those with T/T genotype (p = 0.042). Taken together, these results suggest that the combined T-77C and Arg194Trp genotype of XRCC1 could increase the risk of lung cancer in Taiwanese population. The association of XRCC1 genetic polymorphisms with lung cancer risk could partly mediate through the increase of p53 mutation.
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