Combinational polymorphisms of four DNA repair genes XRCC1, XRCC2, XRCC3, and XRCC4 and their association with oral cancer in Taiwan

Graduate Institute ofNatural Products, Kaohsiung Medical University, Kaohsiung, TaiwanBACKGROUND: Many single nucleotide polymorphisms(SNPs) have been found to be associated with oral cancerbut the biological interactions through SNPs are seldomaddressed. In this study, we focused on the joint effect forSNP combinations of four DNA repair genes, X-rayrepair cross-complementing groups (XRCCs) 1–4,involved in major cancer-related pathways.METHODS: Single nucleotide polymorphism genotypingwas determined using by polymerase chain reaction-restriction fragment length polymorphism in this study(case = 103, control = 98). Different numbers of combi-national SNPs with genotypes called the pseudo-haplo-types from these chromosome-wide genes were used toevaluate their joint effect on oral cancer risk.RESULTS: ExceptforXRCC2rs2040639-AG,noneoftheseSNPs was found to individually contribute to oral cancerrisk. However, for two combined SNPs, the proportion ofsubjects with oral cancer was significantly higher in thepseudo-haplotype with AG-CC genotypes in rs2040639-rs861539 (XRCC2–XRCC3) compared with those withnon-AG-CC genotypes. Similarly, the pseudo-haplotype ofrs2040639–rs861539–rs2075685 (XRCC2–XRCC3–XRCC4)and rs2040639–rs861539–rs2075685–rs1799782 (XRCCs1–4) with specific genotype pattern (AG-CC-TG andCT-AG-CC-TG) among three and four combinationalSNPs were significantly associated with oral cancer. Aftercontrolling for age, gender, smoking, drinking, and betelnut chewing, the estimated odds ratio of oral cancer were2.45, 5.03, and 10.10 for two, three and four specific SNPcombinations, respectively, comparing these specificpseudo-haplotypes to their corresponding non-pseudo-haplotypes.CONCLUSION: We have identified the potential com-bined XRCCs 1–4 SNPs with genotypes that were asso-ciated with oral cancer risk and may have an impact onidentification of a high-risk population.J Oral Pathol Med (2008) 37: 271–277Keywords: DNA repair gene; oral cancer; polymorphism; singlenucleotide polymorphism combination; X-ray repair cross-complementing group