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Nature cancer
09, 2021;2 (9): 962-977.

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
Author Information
  1. Yosuke Tanaka: Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. yotanaka@ncc.go.jp. ORCID
  2. Fumiko Chiwaki: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan. ORCID
  3. Shinya Kojima: Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
  4. Masahito Kawazu: Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
  5. Masayuki Komatsu: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
  6. Toshihide Ueno: Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. ORCID
  7. Satoshi Inoue: Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
  8. Shigeki Sekine: Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
  9. Keisuke Matsusaki: Kanamecho Hospital, Tokyo, Japan.
  10. Hiromichi Matsushita: Department of Laboratory Medicine, National Cancer Center Hospital, Tokyo, Japan.
  11. Narikazu Boku: Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. ORCID
  12. Yae Kanai: Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
  13. Yasushi Yatabe: Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
  14. Hiroki Sasaki: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan. hksasaki@ncc.go.jp. ORCID
  15. Hiroyuki Mano: Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. hmano@ncc.go.jp. ORCID
PMID: 35121863 DOI: 10.1038/s43018-021-00240-6

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.

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MeSH Term

Ascites
Cell Line, Tumor
Humans
Peritoneal Neoplasms
Stomach Neoplasms
Transforming Growth Factor beta

Chemicals

Transforming Growth Factor beta
Journal Article Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000552 (RNA sequence of gastric cancer with malignant ascites [RNA-seq])

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