Abstract
BackgroundGastric 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 MethodsWe 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.ResultsForty-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.ConclusionA 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.
Highlights
Gastric adenocarcinoma is an important contributor to cancer mortality and morbidity, and its molecular mechanism remains largely incomprehensible
Somatic mutation data for 437 gastric adenocarcinoma samples from The Cancer Genome Atlas (TCGA) Stomach Adenocarcinoma (STAD) cohort were extracted by maftools version 1.6.15
We annotated 17,431 protein-coding genes with somatic mutations that mostly consist of missense mutations (Figure 1A), and single-nucleotide polymorphism (SNP) was more common than insertion–deletion (InDel) (Figure 1B)
Summary
Gastric adenocarcinoma is an important contributor to cancer mortality and morbidity, and its molecular mechanism remains largely incomprehensible. Numbers of large-scale genomic analyses on gastric adenocarcinoma have been completed, including The Cancer Genome Atlas (TCGA) project. Surgical resection is still the main means of curative treatment for gastric adenocarcinoma. A portion of patients with advanced gastric adenocarcinoma developed local recurrences and distant metastases and had a poor prognosis after resection [1]. Profiling the genetic mutation of gastric adenocarcinoma that influences the prognosis and accurate risk assessment based on genetic screening will lead to more effective clinical strategies in precision medicine. 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
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