A Four-Gene-Based Risk Score With High Prognostic Value in Gastric Cancer

Bingdong Zhang; Yuerui Li; Liu Yang; Yongbing Chen

doi:10.3389/fonc.2021.584213

A Four-Gene-Based Risk Score With High Prognostic Value in Gastric Cancer

Front Oncol. 2021 Sep 2:11:584213. doi: 10.3389/fonc.2021.584213. eCollection 2021.

Authors

Bingdong Zhang¹, Yuerui Li², Liu Yang³, Yongbing Chen¹

Affiliations

¹ Department of Gastrointestinal Surgery & Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
² Geriatric Cardiology Department of The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army of China General Hospital, Beijing, China.
³ State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing, China.

Abstract

Background: Gastric adenocarcinoma is an important contributor to cancer mortality and morbidity. This study aimed to explore the prognostic value of mutation patterns in gastric adenocarcinoma.

Materials and methods: We extracted somatic mutation data for 437 gastric adenocarcinoma samples from The Cancer Genome Atlas (TCGA) Stomach Adenocarcinoma (STAD) cohort. Kaplan-Meier survival in the R package maftools was used to analyze associations between mutations and survival. Multivariate Cox proportional model was used to establish risk formula. A four-gene-based risk score was developed to predict the overall survival of patients with gastric adenocarcinoma. We used the Tianjin cohort dataset with survival information to further evaluate the clinical value of this mutation signature.

Results: Forty-five survival-related mutated genes were identified and verified, most of which were co-occurring in their mutation pattern and co-occurring with MLH3 and polymerase ϵ (POLE) mutations. Gastric adenocarcinoma samples with the 45 mutated genes had a significantly higher mutation count. Four-gene [UTRN, MUC16, coiled-coil domain-containing protein 178 (CCDC178), and HYDIN] mutation status was used to build a prognostic risk score that could be translated into the clinical setting. The association between the four-gene-based signature and overall survival remained statistically significant after controlling for age, sex, TNM stage, and POLE mutation status in the multivariate model [hazard ratio (HR), 1.88; 95% CI, 1.33-2.7; p < 0.001]. The prognostic significance of the four-gene-based risk score identified in TCGA cohort was validated in the Tianjin cohort.

Conclusion: A four-mutated gene risk formula was developed that correlated with the overall survival of patients with gastric adenocarcinoma using a multivariable Cox regression model. In two independent genomic datasets from TCGA and Tianjin cohorts, low risk scores were associated with higher tumor mutation loads and improved outcome in patients with gastric adenocarcinoma. This finding may have implications for prognostic prediction and therapeutic guidance for gastric adenocarcinoma.

Keywords: gastric cancer; genome; mutations; prognostic value; risk score.