Abstract 1399: Genomic profiling of gastric cancer with peritoneal metastasis identifies molecular subtypes and a potential molecular-guided therapeutic strategy for intractable gastric cancer

Abstract

Abstract Patients with peritoneal metastasis frequently identified in advanced gastric cancer (GC) have a poor prognosis with a median survival of 3-6 months. Because of innate resistance to treatment, these patients have limited therapeutic efficacy and contribute to high mortality. Therefore, it is necessary to understand the molecular characteristics of peritoneal metastasis and search for applicable drugs. This study aims to understand the biological characteristics of peritoneal metastasis in GC through integrative genomic analysis.A total of 66 GC cell lines were used, of which 11 were derived from the stomach, 49 from peritoneal and pleural fluids, and 6 from other origins. Targeted sequencing and RNA sequencing data were obtained from the Songdang Institute for Cancer Research (SICR) database. Cell lines were clustered into EMT and Non-EMT groups according to the expression profiles of 200 genes belonging to the EMT gene set (Nature Cancer, 2021, 2.9: 962-977.). We used gene sets from the Molecular Signatures Database v.7.0.Hierarchical clustering separated the 49 cell lines derived from peritoneal and pleural fluids into two distinct clusters (EMT group, n=20 and Non-EMT group, n=29). Cell lines in the EMT group were classified as GS (65%, 13/20) and CIN (35%, 7/20), whereas cell lines in the Non-EMT group were classified as EBV-positive (3.4%, 1/29), MSI-H (6.9%, 2/29), GS (37.9%, 11/29), and CIN (51.7%, 15/29). The gene set enrichment analysis (GSEA) revealed that gene sets (HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION, CORDENONSI_YAP_CONSERVED_SIGNATURE, and FRIDMAN_SENESCENCE_UP) shows statistically significant differences between the two compared groups. Gene expression levels were significantly different between the EMT and Non-EMT group. In detail, YAP/TEAD pathway related genes (TEAD1, TEAD3, CYR61, DKK1, SLC7A5, SLC2A3) and TGF-β pathway related genes (SMAD3, TGFβ1, TGFβ2, BMP1, INHBA) showed a higher expression level in the EMT group compared to the Non-EMT group (p<0.05). Interestingly, GSEA between the EMT and Non-EMT groups of the GS subtype revealed that gene set CORDENONSI YAP CONSERVED SIGNATURE was enriched in the EMT group. Gene set FOROUTAN_TGFB_EMT_UP, on the other hand, was enriched in the EMT group of the CIN subtype (p<0.05).In conclusion, we identified differences in gene expression levels according to molecular subtypes in GC cell lines with peritoneal metastasis. It can provide useful information to gain new insight into the mechanism of peritoneal metastasis and improve successful treatment options. Furthermore, our results suggest that YAP/TEAD may be considered a potential therapeutic target for GC with peritoneal metastasis. Citation Format: Juin Park, Woo Sun Kwon, Jingmin Che, Tae Soo Kim, Sang Woo Cho, Eun Seo Kim, Hyun Cheol Chung, Sun Young Rha. Genomic profiling of gastric cancer with peritoneal metastasis identifies molecular subtypes and a potential molecular-guided therapeutic strategy for intractable gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1399.