Significant Associations of Mismatch Repair Gene Polymorphisms With Clinical Outcome of Pancreatic Cancer
Significant Associations of Mismatch Repair Gene Polymorphisms With Clinical Outcome of Pancreatic Cancer
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DOI：
10.1200/jco.2008.20.1111
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发表时间：
2009-04-01
影响因子：
45.3
通讯作者：
Li, Donghui
中科院分区：
文献类型：
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作者：
Dong, Xiaoqun;Jiao, Li;Li, Donghui
目的DNA错配修复(MMR)是维持基因组稳定性的关键，可能调节细胞对吉西他滨的反应。我们假设MMR基因变异可能影响胰腺癌患者的临床预后。患者和方法我们评估了1999-2006年间参加吉西他滨为主的术前放化疗II期临床试验的154例胰腺癌患者中8个MMR基因的15个单核苷酸多态(SNPs)。通过Logistic回归和COX比例回归模型评估基因分型与肿瘤治疗反应(再分期时放射学评估肿瘤大小的变化)、切缘阴性肿瘤切除和总生存期的关系。结果在单变量分析中，5、6和10个基因分型分别与肿瘤对术前放化疗的反应、肿瘤可切除性和总生存期显著相关。TREX1EX14-460C>；T和TP73EX2+4G>；A基因仍然是肿瘤疗效的重要预测因素，MLH1 IVS12-169C>；T和TP73仍然是肿瘤可切除性的重要预测因素，EXO1R354H、TREX1和TP73仍然是包括所有临床因素和基因类型的多变量模型中总体生存的重要预测因素。在每个临床终点观察到很强的联合基因效应。例如，在25例不良基因型为0到1的患者中，有20例存活，其中携带2、3、4、5和6至7种不良基因的患者的中位生存期分别为36.2、23.9、16.3、13.0和8.3个月(P<；.001)。结论MMR基因的SNPs对预测放化疗的临床疗效有潜在价值，可作为可切除胰腺癌患者可切除性和总生存期的预后指标。
PurposeDNA mismatch repair (MMR) is critical in maintaining genomic stability and may modulate the cellular response to gemcitabine. We hypothesized that genetic variations in MMR may affect the clinical outcome of patients with pancreatic cancer.Patients and MethodsWe evaluated 15 single-nucleotide polymorphisms (SNPs) of eight MMR genes in 154 patients with potentially resectable pancreatic adenocarcinoma who were enrolled onto phase II clinical trials for preoperative gemcitabine- based chemoradiotherapy from 1999 to 2006. Associations of genotypes with tumor response to therapy (change of tumor size by radiologic evaluation at restaging), margin-negative tumor resection, and overall survival were evaluated using logistic regression and Cox proportional regression models.ResultFive, six, and 10 genotypes were significantly associated with tumor response to preoperative chemoradiotherapy, tumor resectability, and overall survival, respectively, in univariable analysis. TREX1 EX14-460C>T and TP73 Ex2+4G>A genotypes remained as significant predictors for tumor response, MLH1 IVS12-169C>T and TP73 remained as significant predictors for tumor resectability, and EXO1 R354H, TREX1, and TP73 remained as significant predictors for overall survival in multivariable models that included all clinical factors and genotypes examined. A strong combined genotype effect on each clinical end point was observed. For example, 20 of the 25 patients with zero to one adverse genotypes were alive, those with two, three, four, five, and six to seven adverse genotypes had median survival times of 36.2, 23.9, 16.3, 13.0, and 8.3 months, respectively (P < .001).ConclusionSNPs of MMR genes have a potential value as predictors for clinical response to chemoradiotherapy and as prognostic markers for tumor resectability and overall survival of patients with resectable pancreatic cancer.