Construction and evaluation of a polygenic hazard score for prognostic assessment in localized gastric cancer

Abstract

To investigate whether genetic variants may provide additional prognostic value to improve the existing clinical staging system for gastric cancer (GC), we performed two genome-wide association studies (GWASs) of GC survival in the Jiangsu (N=1049) and Shanghai (N=1405) cohorts. By using a TCGA dataset, we validated genetic markers identified from a meta-analysis of these two Chinese cohorts to determine GC survival-associated loci. Then, we constructed a weighted polygenic hazard score (PHS) and developed a nomogram in combination with clinical variables. We also evaluated prognostic accuracy with the time-dependent receiver operating characteristic (ROC) curve, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). We identified a single nucleotide polymorphism (SNP) of rs1618332 at 15q15.1 that was associated with the survival of GC patients with a P value of 4.12×10−8, and we also found additional 25 SNPs having consistent associations among these two Chinese cohort and TCGA cohort. The PHS derived from these 26 SNPs (PHS-26) was an independent prognostic factor for GC survival (all P<0.001). The 5-year AUC of PHS-26 was 0.68, 0.66 and 0.67 for Jiangsu, Shanghai and their pooled cohorts, respectively, which increased to 0.80, 0.82 and 0.81, correspondingly, after being integrated into a nomogram together with variables of the clinical model. The PHS-26 could improve the NRIs by 16.20%, 4.90% and 8.70%, respectively, and the IDIs by 11.90%, 8.00% and 9.70%, respectively. The 26-SNP based PHS could substantially improve the accuracy of prognostic assessment and might facilitate precision medicine for GC patients.