Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response

Ruiping Wang, Shumei Song, Kazuto Harada, Fatemeh Ghazanfari Amlashi, Brian Badgwell, Melissa Pool Pizzi, Yan Xu, Wei Zhao, Xiaochuan Dong, Jiangkang Jin, Ying Wang, Ailing Scott, Lang Ma, Longfei Huo, Diego Vicente, Mariela Blum Murphy, Namita Shanbhag, Ghia Tatlonghari, Irene Thomas, Jane RogersMakoto Kobayashi, Jody Vykoukal, Jeannelyn Santiano Estrella, Sinchita Roy-Chowdhuri, Guangchun Han, Shaojun Zhang, Xizeng Mao, Xingzhi Song, Jianhua Zhang, Jian Gu, Randy L. Johnson, George Adrian Calin, Guang Peng, Ju Seog Lee, Samir M. Hanash, Andrew Futreal, Zhenning Wang, Linghua Wang, Jaffer A. Ajani

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Objective Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets. Design We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs. Results We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: mesenchymal-like' and epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-β as potential therapeutic immune targets. Conclusions We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.

Original languageEnglish (US)
Pages (from-to)18-31
Number of pages14
JournalGut
Volume69
Issue number1
DOIs
Publication statusPublished - Jan 1 2020

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Keywords

  • cancer genetics
  • gastric cancer
  • gastrointestinal cancer
  • gene expression
  • mutations

ASJC Scopus subject areas

  • Gastroenterology

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