Yang J, Wang X, Zou S M, Li H M, Xiao Q, Feng Y R, Huang Y, Feng T, Chen J N, Lin D X, Li Y X, Jin J, Tan W
Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Zhonghua Zhong Liu Za Zhi. 2018 Jun 23;40(6):433-440. doi: 10.3760/cma.j.issn.0253-3766.2018.06.007.
To investigate the associations between genetic variations in DNA mismatch repair genes and sensitivity as well as prognosis to preoperative chemoradiotherapy in patients with locally advanced rectal cancer. Fourteen haplotype-tagging single nucleotide polymorphisms (htSNPs) of MLH1, MLH3 and MSH2 genes were genotyped by Sequenom MassARRAY method in 146 patients with locally advanced rectal cancer who received preoperative chemoradiotherapy. The associations between genotypes and response to capecitabine-based neoadjuvant chemoradiotherapy (nCRT) were measured by odds ratios () and 95% confidence intervals (), adjusted for sex, age, clinical stages and karnofsky performance score (KPS) by unconditional logistic regression model. The survival analyses were performed by the hazard ratios (s) and 95% by Cox proportional regression model. Among 146 cases, 64 patients were nCRT responders with a response rate of 43.8%. MLH3 rs175057 C>T and MSH2 rs13019654 G>T loci were associated with the sensitivity to preoperative chemoradiotherapy. Compared with the rs175057 CC genotype, the adjusted for patients with CT and TT genotypes was 0.42 (95% 0.19-0.91; =0.029). Moreover, for rs13019654, the adjusted for patients with the GT or TT genotypes was 0.49 (95% 0.24-0.98; =0.047) than those with GG genotype. The remaining 12 SNPs, including rs1540354, rs4026175, rs1981929, rs2042649, rs2303428, rs3771273, rs4608577, rs4952887, rs6544991, rs6544997, rs10188090 and rs10191478, were not significantly associated with therapeutic response to preoperative chemoradiotherapy. Meanwhile, MLH3 rs175057 C>T locus was also associated with longer overall survival time in locally advanced rectal cancer (=0.44, 95% 0.20-0.96, =0.038), whereas MSH2 rs3771273 T>A, rs10188090 A>G and rs10191478 T>G loci were associated with shorter overall survival time (=1.74, 95% 1.06-2.84, =0.028; =1.64, 95% 1.01-2.66, =0.046; =1.71, 95% 1.01-2.91, =0.047, respectively). The remaining 10 SNPs, including rs1540354, rs4026175, rs1981929, rs2042649, rs2303428, rs4608577, rs4952887, rs6544991, rs6544997 and rs13019654, were not significantly associated with prognosis. Genetic polymorphisms of MLH3 rs175057 and MSH2 rs13019654 loci can predict the nCRT response, while MLH3 rs175057 as well as MSH2 rs3771273, rs10188090 and rs10191478 may predict prognosis in patients with locally advanced rectal cancer who received preoperative chemoradiotherapy. Therefore, these SNPs could be used as potential genetic markers in the personalized therapy of rectal cancer.
探讨DNA错配修复基因的遗传变异与局部晚期直肠癌患者术前放化疗敏感性及预后之间的关联。采用Sequenom MassARRAY方法对146例接受术前放化疗的局部晚期直肠癌患者的MLH1、MLH3和MSH2基因的14个单倍型标签单核苷酸多态性（htSNP）进行基因分型。通过比值比（OR）和95%置信区间（CI）衡量基因型与基于卡培他滨的新辅助放化疗（nCRT）反应之间的关联，并通过无条件逻辑回归模型对性别、年龄、临床分期和卡诺夫斯基性能评分（KPS）进行校正。通过风险比（HR）和95%CI采用Cox比例回归模型进行生存分析。在146例病例中，64例患者为nCRT反应者，反应率为43.8%。MLH3 rs175057 C>T和MSH2 rs13019654 G>T位点与术前放化疗敏感性相关。与rs175057 CC基因型相比，CT和TT基因型患者的校正OR为0.42（95%CI 0.19 - 0.91；P = 0.029）。此外，对于rs13019654，GT或TT基因型患者的校正OR为0.49（95%CI 0.24 - 0.98；P = 0.047），低于GG基因型患者。其余12个SNP，包括rs1540354、rs4026175、rs1981929、rs2042649、rs2303428、rs3771273、rs4608577、rs4952887、rs6544991、rs6544997、rs10188090和rs10191478，与术前放化疗的治疗反应无显著关联。同时，MLH3 rs175057 C>T位点也与局部晚期直肠癌患者较长的总生存时间相关（HR = 0.44，95%CI 0.20 - 0.96，P = 0.038），而MSH2 rs3771273 T>A、rs10188090 A>G和rs10191478 T>G位点与较短的总生存时间相关（HR分别为1.74，95%CI 1.06 - 2.84，P = 0.028；HR = 1.64，95%CI 1.01 - 2.66，P = 0.046；HR = 1.71，95%CI 1.01 - 2.91，P = 0.047）。其余10个SNP，包括rs1540354、rs4026175、rs1981929、rs2042649、rs2303428、rs4608577、rs4952887、rs6544991、rs6544997和rs13019654，与预后无显著关联。MLH3 rs175057和MSH2 rs13019654位点的基因多态性可预测nCRT反应，而MLH3 rs175057以及MSH2 rs3771273、rs10188090和rs10191478可能预测接受术前放化疗的局部晚期直肠癌患者的预后。因此，这些SNP可作为直肠癌个体化治疗中的潜在遗传标志物。
