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. 2022 Nov 9;4(5):1331-1338.
doi: 10.1016/j.fmre.2022.09.031. eCollection 2024 Sep.

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

Jing Ni  1   2   3 , Mengyun Wang  4   5 , Tianpei Wang  1   2   6 , Caiwang Yan  1   2   7 , Chuanli Ren  8 , Gang Li  9 , Yanbing Ding  10 , Huizhang Li  11 , Lingbin Du  11 , Yue Jiang  1   2 , Jiaping Chen  1   2 , Yanong Wang  12 , Dazhi Xu  12 , Meng Zhu  1   2   13 , Juncheng Dai  1   2 , Hongxia Ma  1   2 , Zhibin Hu  1   2   6 , Hongbing Shen  1   2   11 , Qingyi Wei  4   14   15 , Guangfu Jin  1   2   13
Affiliations

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

Jing Ni et al. Fundam Res. .

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.

Keywords: Genome-wide association study; Nomogram; Polygenic hazard score; Stomach neoplasm; Survival.

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Conflict of interest statement

The authors declare that they have no conflicts of interest in this work.

Figures

Image, graphical abstract
Graphical abstract
Fig 1
Fig 1
The most significant locus at 15q15.1 was associated with the overall survival of gastric cancer. (a) A regional association plot is shown for the 15q15.1 locus; (b) The lead variant rs1618332 was consistently associated with overall survival of gastric cancer in the Jiangsu and Shanghai cohorts and TCGA dataset.
Fig 2
Fig 2
Nomogram construction and evaluation for gastric cancer overall survival. (a) The nomogram for 3-year or 5-year overall survival prediction based on four independent prognostic factors in the pooled cohort (n = 2454); (b-c) Calibration curves of the nomogram to predict overall survival at 3- and 5-years in the pooled cohort (n = 2454). OS, overall survival.
Fig 3
Fig 3
Time-dependent ROC curves and AUCs at 5-years were used to assess the prognostic accuracy of the nomogram and other clinical prognostic factors. (a) Jiangsu cohort (n = 1049); (b) Shanghai cohort (n = 1405); (c) Pooled cohort (n = 2454); (d) TCGA dataset (n = 343).
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