Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes

Abstract

Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

“…However, in this case, the underlying family predisposing gene was CTNNA1 and not CDH1 [39], and somatic mutations at LMTK3, MCTP2, MED12, PIK3CA, and ARID1A genes have been demonstrated, as well as mutations in other genes recently shown to be part of the molecular signatures of sporadic GC [54][55][56][57][58][59]. Similar studies in a series of HDGC caused either by CDH1 or CTNNA1 germline mutations, and in different progression stages, would undoubtedly help to disclose the somatic mutation landscape of this disease.…”

“…In sporadic GC, p53 nuclear overexpression by IHC, was found both in intestinal and diffuse GCs and was correlated with tumour progression, poor prognosis and unfavourable response to therapy [84][85][86][87][88][89]. Moreover, NGS studies have identified TP53 mutations as one of the most frequently alterations in GCs, and TP53 has been pointed as a candidate driver gene, especially in intestinal-type GC [54,[56][57][58]90]. The evidence of p53 nuclear accumulation in our study suggests that TP53 may be a key gene involved in GC progression, also in the hereditary setting.…”

Accumulation of Somatic Mutations in TP53 in Gastric Epithelium With Helicobacter pylori Infection

“…Recent reports demonstrated that human gastric cancer has approximately 66 to 212 mutations in coding regions, and only a few of them are considered driver mutations [3][4][5][6] . Among them, mutations in the tumor suppressor TP53 gene are the most common driver mutations in human gastric cancer tissues.…”

Germline genetic variants were interactively associated with somatic alterations in gastric cancer

“…Gastric cancer driver genes were obtained from 3 sources: (1) 16 gastric cancer‐related driver genes from Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census(v78)31; (2) 175 driver genes of gastric cancer from the Integrative Onco Genomics (IntOGen) database32; (3) 108 significantly mutated genes (SMGs) and 26 somatic copy number alteration genes from previously published Whole Genome Sequencing (WGS) or Whole Exome Sequencing (WES) articles 4, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22…”

“…These studies have identified many driver genes, whose mutations confer selective growth advantage to tumor 11. Some of these driver genes are previously known cancer genes (eg, TP53 , ARID1A, and CDH1 ), while the others are new‐found significantly mutated genes in gastric cancer (eg, MUC6 , CTNNA2 , GLI3, and RNF43 ) 4, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. Moreover, the copy number changes and characteristic mutational signatures also play important roles in gastric cancer development 4, 16, 17, 18, 19…”