Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Mol Carcinog. 2012 Jun;51(6):491-9. doi: 10.1002/mc.20817. Epub 2011 Jun 16.
DNA repair plays a critical role in human cancers. We hypothesized that DNA mismatch repair gene variants are associated with risk of pancreatic cancer. We retrospectively genotyped 102 single-nucleotide polymorphisms (SNPs) of 13 mismatch repair related genes in 706 patients with pancreatic cancer and 706 cancer-free controls using the mass spectroscopy-based MassArray method. Association of genotype with pancreatic cancer risk was tested by multivariate logistic regression models. A significance level of P ≤ 0.0015 was set at the false discovery rate (FDR) <1% using the Beta-Uniform Mixture method. We found 28 SNPs related to altered pancreatic cancer risk (P < 0.05). Adjusting for multiple comparisons, MGMT I143V AG/GG, PMS2 IVS1-1121C > T TC/TT, and PMS2L3 Ex1 + 118C > T CT/TT genotypes showed significant main effects on pancreatic cancer risk at FDR <1% with OR (95% CI) of 0.60 (0.46-0.80), 1.44 (1.14-1.81), and 5.54 (2.10-14.61), respectively (P ≤ 0.0015). To demonstrate genotype-phenotype association, we measured O(6)-ethylguanosine (O(6)-EtGua) adduct levels in vitro by immunoslot blot assay in lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in 297 case/control subjects. MGMT I143V GG, MGMT K178R GG, MSH6 G39E AG/AA, PMS2L3 IVS3 + 9A > G GA and TP73 IVS1-7449G > C CG/CC genotypes correlated with a higher level of ENU-induced DNA adducts. Haplotypes of MGMT, MSH6, PMS2, PMS2L3, and TP73 were significantly associated with pancreatic cancer risk (P ≤ 0.0015). Our findings suggest that mismatch repair gene variants may affect susceptibility to pancreatic cancer.
DNA 修复在人类癌症中起着关键作用。我们假设 DNA 错配修复基因变异与胰腺癌风险相关。我们使用基于质谱的 MassArray 方法，对 706 名胰腺癌患者和 706 名无癌对照者的 13 个错配修复相关基因中的 102 个单核苷酸多态性（SNP）进行了回顾性基因分型。使用多元逻辑回归模型检验基因型与胰腺癌风险的关联。使用 Beta-Uniform Mixture 方法，将 FDR<1%的假发现率（P≤0.0015）设定为显著性水平。我们发现 28 个 SNP 与改变的胰腺癌风险相关（P<0.05）。在进行多次比较调整后，MGMT I143V AG/GG、PMS2 IVS1-1121C>T TC/TT 和 PMS2L3 Ex1+118C>T CT/TT 基因型对胰腺癌风险的主要影响在 FDR<1%时具有统计学意义，OR（95%CI）分别为 0.60（0.46-0.80）、1.44（1.14-1.81）和 5.54（2.10-14.61）（P≤0.0015）。为了证明基因型-表型关联，我们在 297 例病例/对照者的淋巴细胞中用免疫斑点印迹分析测定了 N-乙基-N-亚硝脲（ENU）处理后 O(6)-乙基鸟嘌呤（O(6)-EtGua）加合物的水平。MGMT I143V GG、MGMT K178R GG、MSH6 G39E AG/AA、PMS2L3 IVS3+9A>G GA 和 TP73 IVS1-7449G>C CG/CC 基因型与更高水平的 ENU 诱导的 DNA 加合物相关。MGMT、MSH6、PMS2、PMS2L3 和 TP73 的单体型与胰腺癌风险显著相关（P≤0.0015）。我们的研究结果表明，错配修复基因变异可能影响胰腺癌的易感性。
