Xiaohui Zhao1,2, Dongfang Dai1, Xiaoqin Li1, Bo Shen3, Xiaofeng Chen4, Yongqian Shu5, Deqiang Wang6,7. 1. Department of Medical Oncology, The Cancer Therapy Center, Affiliated Hospital of Jiangsu University, Road Jiefang, Zhenjiang, 212001, Jiangsu, China. 2. Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China. 3. Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. 4. Department of Medical Oncology, The First Affiliated Hospital of Nanjing Medical University, Road Guangzhou, Nanjing, 210029, China. 5. Department of Medical Oncology, The First Affiliated Hospital of Nanjing Medical University, Road Guangzhou, Nanjing, 210029, China. shuyongqian@csco.org.cn. 6. Department of Medical Oncology, The Cancer Therapy Center, Affiliated Hospital of Jiangsu University, Road Jiefang, Zhenjiang, 212001, Jiangsu, China. deqiang_wang@aliyun.com. 7. Department of Medical Oncology, The First Affiliated Hospital of Nanjing Medical University, Road Guangzhou, Nanjing, 210029, China. deqiang_wang@aliyun.com.
Abstract
BACKGROUND: Defective mismatch repair (dMMR) and microsatellite instability (MSI) correlate with gastric cancer (GC) outcome. We hypothesized that MMR genetic polymorphisms that have low-penetrant effects but may cause heterogeneous MMR capability among individuals also affect GC outcome. METHODS: The polymorphisms rs1800734 in MLH1, rs2303428 and rs3732183 in MSH2, rs735943 in EXO1, and rs11797 in TREX1 were selected and analyzed in independent discovery and validation sets that included 167 and 593 patients, respectively. MSI was determined. RESULTS: In both the discovery and validation sets, the rs2303428 TC + CC genotype correlated with poor overall survival (OS) in non-cardia (P < 0.05) but not in cardia GC. Multivariate models showed that for OS of patients with non-cardia GC, the rs2303428 TC + CC genotype was an independent predictor in the validation set (HR 1.54; 95% CI 1.02-2.32; P = 0.040) and had a trend to be an independent predictor in the discovery set (HR 1.70; 95% CI 0.96-3.01; P = 0.067). Furthermore, in both patient sets, fluoropyrimidines-based adjuvant chemotherapy improved OS for non-cardia patients with the rs2303428 TC + CC genotype (HR 0.14; 95% CI 0.04-0.57; P = 0.006; and HR 0.29; 95% CI 0.15-0.58; P < 0.001, respectively) but not for those with the TT genotype. The rs2303428 genotypes were not associated with MSI frequency. The rs2303428 TC + CC genotype correlated with reduced expressions for thymidylate synthetase, P-glycoprotein and ERCC1 (P < 0.05) in non-cardia GC. CONCLUSIONS: The rs2303428 genotypes may predict prognosis and adjuvant chemotherapy benefit in non-cardia GC patients.
BACKGROUND: Defective mismatch repair (dMMR) and microsatellite instability (MSI) correlate with gastric cancer (GC) outcome. We hypothesized that MMR genetic polymorphisms that have low-penetrant effects but may cause heterogeneous MMR capability among individuals also affect GC outcome. METHODS: The polymorphisms rs1800734 in MLH1, rs2303428 and rs3732183 in MSH2, rs735943 in EXO1, and rs11797 in TREX1 were selected and analyzed in independent discovery and validation sets that included 167 and 593 patients, respectively. MSI was determined. RESULTS: In both the discovery and validation sets, the rs2303428TC + CC genotype correlated with poor overall survival (OS) in non-cardia (P < 0.05) but not in cardia GC. Multivariate models showed that for OS of patients with non-cardia GC, the rs2303428TC + CC genotype was an independent predictor in the validation set (HR 1.54; 95% CI 1.02-2.32; P = 0.040) and had a trend to be an independent predictor in the discovery set (HR 1.70; 95% CI 0.96-3.01; P = 0.067). Furthermore, in both patient sets, fluoropyrimidines-based adjuvant chemotherapy improved OS for non-cardiapatients with the rs2303428TC + CC genotype (HR 0.14; 95% CI 0.04-0.57; P = 0.006; and HR 0.29; 95% CI 0.15-0.58; P < 0.001, respectively) but not for those with the TT genotype. The rs2303428 genotypes were not associated with MSI frequency. The rs2303428TC + CC genotype correlated with reduced expressions for thymidylate synthetase, P-glycoprotein and ERCC1 (P < 0.05) in non-cardia GC. CONCLUSIONS: The rs2303428 genotypes may predict prognosis and adjuvant chemotherapy benefit in non-cardia GC patients.
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