DNA mismatch repair network gene polymorphism as a susceptibility factor for pancreatic cancer.
DNA mismatch repair network gene polymorphism as a susceptibility factor for pancreatic cancer.
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DOI：
10.1002/mc.20817
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发表时间：
2012-06
影响因子：
4.6
通讯作者：
Li, Donghui
中科院分区：
文献类型：
--
作者：
Dong, Xiaoqun;Li, Yanan;Chang, Ping;Hess, Kenneth R.;Abbruzzese, James L.;Li, Donghui
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例胰腺癌患者和706例无癌对照的13个错配修复相关基因的102个单核苷酸多态性（SNP）进行了回顾性基因分型。基因型与胰腺癌风险的关系通过多变量logistic回归模型进行检验。使用β-均匀混合法，将P≤0.0015的显著性水平设定为错误发现率（FDR）<1%。我们发现28个SNPs与胰腺癌风险改变有关（P<0.05）。多重比较校正后，MGMT I143 V AG/GG、PMS 2 IVS 1 - 1121 C>T TC/TT和PMS 2L 3 Ex 1 + 118 C>T CT/TT基因型在FDR <1%时对胰腺癌风险有显著的主效应，OR（95% CI）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-表型相关性，我们在297例病例/对照受试者中通过免疫印迹法测定了N-乙基-N-亚硝基脲（ENU）处理的淋巴细胞中O 6-乙基鸟苷（O 6-EtGua）加合物水平。MGMT I143 V GG、MGMT K178 R GG、MSH 6 G39 E AG/AA、PMS 2L 3 IVS 3 +9A>G GA和TP 73 IVS 1 - 7449 G> CG/CC基因型与较高水平的ENU诱导的DNA加合物相关。MGMT、MSH 6、PMS 2、PMS 2L 3和TP 73单倍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会影响胰腺癌的易感性。
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 O6-ethylguanosine (O6-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.
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影响因子：
45.3
作者：
Dong, Xiaoqun;Jiao, Li;Li, Donghui
通讯作者：
Li, Donghui
影响因子：
14.9
作者：
Lee, Phil Hyoun;Shatkay, Hagit
通讯作者：
Shatkay, Hagit
影响因子：
3.8
作者：
McWilliams, Robert R.;Bamlet, William R.;Petersen, Gloria M.
通讯作者：
Petersen, Gloria M.
DOI：
10.1073/pnas.0811991106
发表时间：
2009-01-13
影响因子：
11.1
作者：
Klapacz, Joanna;Meira, Lisiane B.;Samson, Leona D.
通讯作者：
Samson, Leona D.
影响因子：
4.8
作者：
Doherty, KM;Sharma, S;Brosh, RM
通讯作者：
Brosh, RM