Comprehensive molecular characterization of gastric adenocarcinoma

Abstract

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.

Programmed Death-Ligand 1 Expression, Microsatellite Instability, Epstein–Barr Virus, and Human Papillomavirus in Nasopharyngeal Carcinomas of Patients from the Philippines

“…PD-L1 expression was described in other EBV-associated malignancies [11][12][13] and several studies have reported positive PD-L1 expression in 25-89% of NPCs [14][15][16][17]. In contrast to EBV-associated gastric adenocarcinomas in which expression of PD-L1 protein may result from PD-L1 gene amplification [18], NPCs do not have PD-L1 gene copy number change [19]. PD-L1 expression is shown to be associated with either constitutive oncogenic activation mediated by EBV-encoded latent-membrane protein 1, or through interferon-c signaling pathways [16].…”

Mismatch repair deficiency may affect clinical outcome through immune response activation in metastatic gastric cancer patients receiving first-line chemotherapy

“…Recently, researchers from The Cancer Genome Atlas [4] proposed a categorization of gastric cancer into four major subtypes: Epstein-Barr virus related, microsatellite instable (MSI), genomically stable, and chromosomally instable. The MSI category, presenting a typical lack of function of the mismatch repair (MMR) genes (mainly MLH1 and MSH2), is of clinical interest because of the favorable prognostic profile of such tumors compared with their MMR-proficient counterpart.…”

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…”

“…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…”