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

Yosuke Tanaka, Fumiko Chiwaki, Shinya Kojima, Masahito Kawazu, Masayuki Komatsu, Toshihide Ueno, Satoshi Inoue, Shigeki Sekine, Keisuke Matsusaki, Hiromichi Matsushita, Narikazu Boku, Yae Kanai, Yasushi Yatabe, Hiroki Sasaki, Hiroyuki Mano

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)962-977
Number of pages16
JournalNature Cancer
Volume2
Issue number9
DOIs
Publication statusPublished - 2021 Sep

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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