Multi-omic profiling of peritoneal metastases in gastric cancer identifies molecular subtypes and therapeutic vulnerabilities

• Published in: Nature cancer Vol. 2; no. 9; pp. 962 - 977
• Main Authors: Tanaka, Yosuke, Chiwaki, Fumiko, Kojima, Shinya, Kawazu, Masahito, Komatsu, Masayuki, Ueno, Toshihide, Inoue, Satoshi, Sekine, Shigeki, Matsusaki, Keisuke, Matsushita, Hiromichi, Boku, Narikazu, Kanai, Yae, Yatabe, Yasushi, Sasaki, Hiroki, Mano, Hiroyuki
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.09.2021
• Subjects: Algorithms; Ascites; Cancer therapies; Chemotherapy; Gastric cancer; Genes; Genomes; Kinases; Metastasis; Mutation; Tumors; Hong Kong China; China
• DOI: 10.1038/s43018-021-00240-6

Peritoneal metastasis, a hallmark of incurable advanced gastric cancer (GC), presently has no curative therapy and its molecular features have not been examined extensively. Here we present a comprehensive multi-omic analysis of malignant ascitic fluid samples and their corresponding tumor cell lines from 98 patients, including whole-genome sequencing, RNA sequencing, DNA methylation and enhancer landscape. We identify a higher frequency of receptor tyrosine kinase and mitogen-activated protein kinase pathway alterations compared to primary GC; moreover, approximately half of the gene alterations are potentially treatable with targeted therapy. Our analyses also stratify ascites-disseminated GC into two distinct molecular subtypes: one displaying active super enhancers (SEs) at the ELF3, KLF5 and EHF loci, and a second subtype bearing transforming growth factor-β (TGF-β) pathway activation through SMAD3 SE activation and high expression of transcriptional enhancer factor TEF-1 (TEAD1). In the TGF-β subtype, inhibition of the TEAD pathway circumvents therapy resistance, suggesting a potential molecular-guided therapeutic strategy for this subtype of intractable GC.