Whole-exome sequencing identifies prognostic mutational signatures in gastric cancer

Abstract

Background: Gastric cancer (GC) is a heterogeneous disease, and is a leading cause of cancer deaths in Eastern Asia. Genomic analysis, such as whole-exome sequencing (WES), can help identify key genetic alterations leading to the malignancy and diversity of GC, and may help identify new drug targets.

Methods: We identified genomic alterations in a cohort of 38 GC patients, including 26 metastatic and 12 non-metastatic patients. We analyzed the association between novel gene mutations and copy number variations (CNVs) with tumor metastasis and patient survival.

Results: A number of significantly mutated genes in somatic and germline cells were identified. Among them, ATAD3B somatic mutation, a potential biomarker of immunotherapy in stomach cancers, was associated with better patient survival (P=0.0939) and metastasis (P=0.074). POLE germline variation was correlated with shorter overall survival (OS; P=0.0100). Novel CNVs were also identified and can potentially be used as biomarkers. These included 9p24.1 deletion (P=0.0376) and 16p11.2 amplification (P=0.0066), which were both associated with shorter OS. CNVs of several genes including MMP9, PTPN1, and SS18L1 were found to be significantly related to metastasis (P<0.05).

Conclusions: We characterized the mutational landscape of 38 GC patients and discovered several potential new predictive markers of survival and metastasis in GC.

Keywords: Whole-exome sequencing (WES); copy number variations (CNV); germline mutation; somatic mutation; tumor mutation burden.

Figure 1

Significant somatic mutated genes in gastric cancer (GC). (A) High frequency somatic gene mutations of metastatic (blue) and non-metastatic (red) patients; (B) significantly mutated genes between the metastatic and non-metastatic groups; (C) comparison of the high frequency mutated genes in this study with the TCGA-STAD cohort; (D) Kaplan-Meier survival curve of patients with an ATAD3B mutation, P=0.0939 (log-rank test).

Figure 2

Germline variants with significant differences in distribution between metastatic and non-metastatic groups. (A) Oncoplot of top mutated genes with germline variants in metastatic patients and non-metastatic patients; (B) survival curve of patients with POLE germline mutations, P=0.0100 (log-rank test); (C) the site and distribution of POLE germline mutations.

Figure 3

Association between somatic cytoband copy number alteration and patient metastatic and survival status. (A) Cytoband with high frequency copy number alteration in the metastatic and non-metastatic patients; (B,C) survival curve of patients with 16p amplification (B, P=0.0143, log-rank test), and 17p deletion (C, P=0.0939, log-rank test); (D) forest plot of cytoband with a significant distribution difference in copy number alterations between the metastatic and non-metastatic groups; (E,F) Kaplan-Meier survival curve of patients with 9p24.1 deletion (E, P=0.0376, log-rank test), and 16p11.2 amplification (F, P=0.0066, log-rank test).

Figure 4

Association between somatic copy number variants (CNVs) and patient metastasis. (A) Genes with high frequency copy number alterations in metastatic and non-metastatic patients; (B) forest plot of significant CNV genes between the metastatic and non-metastatic groups; (C) comparison of the high frequency CNV genes between this study and the TCGA-STAD cohort; (D) survival curve of patients with ERBB2 amplification (P=0.2463).