Genetic variations in MLH3 and MSH2 genes are associated with the sensitivity and prognosis in locally advanced rectal cancer patients receiving preoperative chemoradiotherapy
10.3760/cma.j.issn.0253-3766.2018.06.007
- VernacularTitle: MLH3和MSH2遗传变异与直肠癌患者术前同步放化疗敏感性和生存的关系
- Author:
Jie YANG
1
;
Xin WANG
2
;
Shuangmei ZOU
3
;
Hongmin LI
1
;
Qin XIAO
2
;
Yanru FENG
2
;
Ying HUANG
1
;
Ting FENG
1
;
Jinna CHEN
1
;
Dongxin LIN
1
;
Yexiong LI
2
;
Jing JIN
2
;
Wen TAN
1
Author Information
1. 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
2. Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
3. Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Publication Type:Clinical Trail
- Keywords:
Neoplasms, rectal;
Polymorphism, single nucleotide;
MLH3;
MSH2;
Preoperative chemoradiotherapy;
Sensitivity;
Prognosis
- From:
Chinese Journal of Oncology
2018;40(6):433-440
- CountryChina
- Language:Chinese
-
Abstract:
Objective: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.
Methods: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 (ORs) and 95% confidence intervals (CIs), 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 (HRs) and 95% CIs by Cox proportional regression model.
Results: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 OR for patients with CT and TT genotypes was 0.42 (95% CI: 0.19-0.91; P=0.029). Moreover, for rs13019654, the adjusted OR for patients with the GT or TT genotypes was 0.49 (95% CI: 0.24-0.98; P=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 (HR=0.44, 95% CI: 0.20-0.96, P=0.038), whereas MSH2 rs3771273 T>A, rs10188090 A>G and rs10191478 T>G loci were associated with shorter overall survival time (HR=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, respectively). The remaining 10 SNPs, including rs1540354, rs4026175, rs1981929, rs2042649, rs2303428, rs4608577, rs4952887, rs6544991, rs6544997 and rs13019654, were not significantly associated with prognosis.
Conclusions: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.
