Is there a dose-dependent effect of genetic susceptibility loci for gastric cancer on prognosis of the patients?

// Lei Cheng 1,2,* , Li-Xin Qiu 1,2,3,* , Ming Jia 1,2,* , Fei Zhou 1,2 , Meng-Yun Wang 1,2 , Ruo-Xin Zhang 1,2 , Yajun Yang 4,5 , Xiaofeng Wang 4,5 , Jiucun Wang 4,5 , Li Jin 4,5 and Qing-Yi Wei 1,2,6 1 Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Xuhui, Shanghai, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Xuhui, Shanghai, China 3 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Xuhui, Shanghai, China 4 Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China 5 Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China 6 Duke Cancer Institute, Duke University Medical Center, and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA * These authors have contributed equally to this work Correspondence to: Qing-Yi Wei, email: // Keywords : gastric cancer, genome-wide association study, genetic risk score, prognosis Received : May 30, 2016 Accepted : October 14, 2016 Published : November 04, 2016 Abstract Literature suggests that genetic variants associated with increased susceptibility to gastric cancer (GCa) are mostly located in genes involved in carcinogenesis and possibly tumor progression. Therefore, we hypothesize that high genetic susceptibility is also associated with prognosis of the patients. To test this hypothesis, we selected a total of 42 common genetic variants that were reportedly associated with GCa risk with a high level of evidence obtained from either genome-wide association studies (GWASs) or meta-analyses and performed survival analysis of patients used in a case-control analysis. We first used 1115 GCa cases and 1172 cancer-free controls of ethnic Han Chinese to construct a weighted genetic risk score (GRS). Then, we included 633 GCa cases with available clinical information, fit GRS in a fractional polynomial Cox proportional hazards regression model to investigate whether there is a dose-dependent effect of GRS on risk of death in survival analysis. Dynamic predictive value of genetic risk for prognosis was also calculated. The results showed that the increase of GRS had no effect on risk of death in these GCa patients. Compared with GCa patients with the medium GRS, there was no significant difference in survival in patients with either a low ( P = 0.349) or a high ( P = 0.847) GRS. The results unchanged when data were stratified by tumor stage and Lauren’s classification. Time-dependent predictive value for prognosis in considering both clinical factors and GRS was comparable with that in considering clinical factors alone, for either all patients ( P = 0.986) or stage- and Laruen type-based subgroups ( P > 0.05 for all). In conclusion, higher polygenic susceptibility loci for GCa may not indicate worse prognosis of Chinese patients. Additional variants of relevant genes modulating GCa patients’ survival need to be further identified.