Comprehensive SNP Scan of DNA Repair and DNA Damage Response Genes Reveal Multiple Susceptibility Loci Conferring Risk to Tobacco Associated Leukoplakia and Oral Cancer

Polymorphic variants of DNA repair and damage response genes play major role in carcinogenesis. These variants are suspected as predisposition factors to Oral Squamous Cell Carcinoma (OSCC). For identification of susceptible variants affecting OSCC development in Indian population, the “maximally informative” method of SNP selection from HapMap data to non-HapMap populations was applied. Three hundred twenty-five SNPs from 11 key genes involved in double strand break repair, mismatch repair and DNA damage response pathways were genotyped on a total of 373 OSCC, 253 leukoplakia and 535 unrelated control individuals. The significantly associated SNPs were validated in an additional cohort of 144 OSCC patients and 160 controls. The rs12515548 of MSH3 showed significant association with OSCC both in the discovery and validation phases (discovery P-value: 1.43E-05, replication P-value: 4.84E-03). Two SNPs (rs12360870 of MRE11A, P-value: 2.37E-07 and rs7003908 of PRKDC, P-value: 7.99E-05) were found to be significantly associated only with leukoplakia. Stratification of subjects based on amount of tobacco consumption identified SNPs that were associated with either high or low tobacco exposed group. The study reveals a synergism between associated SNPs and lifestyle factors in predisposition to OSCC and leukoplakia.DNA修复与损伤应答基因的多态性变异在致癌过程中发挥关键作用。此类变异被推测为口腔鳞状细胞癌（Oral Squamous Cell Carcinoma，OSCC）的易感因素。为在印度人群中鉴定影响OSCC发生的易感变异，本研究采用了从国际人类基因组单体型图计划（HapMap）数据向非HapMap人群筛选单核苷酸多态性（Single Nucleotide Polymorphism，SNP）的“最大信息量”方法。本研究对参与双链断裂修复、错配修复及DNA损伤应答通路的11个关键基因的325个SNP位点进行基因分型，共纳入373例OSCC患者、253例口腔白斑病患者及535名无关对照个体。将与OSCC显著相关的SNP位点在额外的144例OSCC患者及160名对照个体组成的队列中进行验证。MSH3基因的rs12515548位点在发现阶段与验证阶段均表现出与OSCC的显著关联（发现阶段P值：1.43×10^-5，重复验证阶段P值：4.84×10^-3）。另有两个SNP位点——MRE11A基因的rs12360870（P值：2.37×10^-7）与PRKDC基因的rs7003908（P值：7.99×10^-5）——仅与口腔白斑病存在显著关联。基于烟草暴露量对研究对象进行分层分析后，鉴定出分别与高烟草暴露组和低烟草暴露组相关的SNP位点。本研究揭示，在OSCC与口腔白斑病的易感机制中，相关SNP位点与生活方式因素存在协同作用。