Genomics Score Based on Genome-Wide Network Analysis for Prediction of Survival in Gastric Cancer: A Novel Prognostic Signature

Abstract

Purpose: Gastric cancer (GC) is a product of multiple genetic abnormalities, including genetic and epigenetic modifications. This study aimed to integrate various biomolecules, such as miRNAs, mRNA, and DNA methylation, into a genome-wide network and develop a nomogram for predicting the overall survival (OS) of GC. Materials and Methods: A total of 329 GC cases, as a training cohort with a random of 150 examples included as a validation cohort, were screened from The Cancer Genome Atlas database. A genome-wide network was constructed based on a combination of univariate Cox regression and least absolute shrinkage and selection operator analyses, and a nomogram was established to predict 1-, 3-, and 5-year OS in the training cohort. The nomogram was then assessed in terms of calibration, discrimination, and clinical usefulness in the validation cohort. Afterward, in order to confirm the superiority of the whole gene network model and further reduce the biomarkers for the improvement of clinical usefulness, we also constructed eight other models according to the different combinations of miRNAs, mRNA, and DNA methylation sites and made corresponding comparisons. Finally, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were also performed to describe the function of this genome-wide network. Results: A multivariate analysis revealed a novel prognostic factor, a genomics score (GS) comprising seven miRNAs, eight mRNA, and 19 DNA methylation sites. In the validation cohort, comparing to patients with low GS, high-GS patients (HR, 12.886; P < 0.001) were significantly associated with increased all-cause mortality. Furthermore, after stratification of the TNM stage (I, II, III, and IV), there were significant differences revealed in the survival rates between the high-GS and low-GS groups as well (P < 0.001). The 1-, 3-, and 5-year C-index of whole genomics-based nomogram were 0.868, 0.895, and 0.928, respectively. The other models have comparable or relatively poor comprehensive performance, while they had fewer biomarkers. Besides that, DAVID 6.8 further revealed multiple molecules and pathways related to the genome-wide network, such as cytomembranes, cell cycle, and adipocytokine signaling. Conclusion: We successfully developed a GS based on genome-wide network, which may represent a novel prognostic factor for GC. A combination of GS and TNM staging provides additional precision in stratifying patients with different OS prognoses, constituting a more comprehensive sub-typing system. This could potentially play an important role in future clinical practice.