Abstract 844: Integrated analysis of genetic and epigenetic alterations in gastric carcinomas

Abstract

Abstract Gastric carcinomas (GCs) have highly heterogeneous features in terms of clinical phenotypes, histological characters and molecular mechanisms. In our previous study based on Infinium HumanMethylation27 BeadChip, unsupervised hierarchical clustering analysis using genome-wide DNA methylation profiles of non-tumorous gastric mucosa (N) samples, being at the precancerous condition of GC, divided 110 GC patients into 3 subclusters. This epigenomic clustering based on DNA methylation profiles of N samples showed significant correlations with clinicopathological features of the corresponding carcinomas: For example, GCs belonging to Cluster B1 showed poorer differentiated histology, tumor aggressiveness and poorer outcome. To gain a further understanding of gastric carcinogenesis, we performed integrative analysis of genomics and epigenomics. Whole exome sequencing and single-nucleotide polymorphism microarray analysis were performed in 66 paired samples of GC and the corresponding N from the same patients of the previous epigenomic study. The datasets were analyzed by MutSigCV and GISTIC2.0 pipelines and significant accumulations of single nucleotide variation, insertion, deletion and copy number variation were identified within each of the epigenomic subclusters. Then we performed a pathway enrichment analysis using the genes genetically and epigenetically altered in each subcluster. Somatic mutation of the TP53, SMAD4, or ARID1A genes, which had been well known to occur in GCs, appeared with the same frequencies in 3 subclusters. On the other hand, a certain gene which has rarely reported before was recurrently mutated in our cohort. Epigenetic Cluster B1 was characterized by a fewer copy number alterations, and particularly by amplifications of 17q12, 10p11.1 and 3q26.2, including the genomic region of oncogene ERBB2. In integrated pathway enrichment analysis, p53-related pathways were enriched in Cluster A, and epithelial-mesenchymal transition (EMT)-related pathways were enriched in this particular Cluster B1. Poorly differentiated histological phenotype, i.e. loss of cell polarity or epithelial cell adhesion, may be attributable to molecular signature relating to EMT in Cluster B1. These data indicate that genetic and epigenetic alterations cooperate on gastric carcinogenesis thus impact on tumor aggressiveness. The consistency of molecular characteristics and pathological phenotypes suggests the possibility that future malignant progression can be predicted based on genetic and epigenetic alterations even at early stage of gastric carcinogenesis. Citation Format: Menghan Yang, Eri Arai, Hiromi Sakamoto, Hirohiko Totsuka, Hirokazu Taniguchi, Hitoshi Katai, Teruhiko Yoshida, Yae Kanai. Integrated analysis of genetic and epigenetic alterations in gastric carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 844.