TY - JOUR T1 - Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response JF - Gut JO - Gut DO - 10.1136/gutjnl-2018-318070 SP - gutjnl-2018-318070 AU - Ruiping Wang AU - Shumei Song AU - Kazuto Harada AU - Fatemeh Ghazanfari Amlashi AU - Brian Badgwell AU - Melissa Pool Pizzi AU - Yan Xu AU - Wei Zhao AU - Xiaochuan Dong AU - Jiangkang Jin AU - Ying Wang AU - Ailing Scott AU - Lang Ma AU - Longfei Huo AU - Diego Vicente AU - Mariela Blum Murphy AU - Namita Shanbhag AU - Ghia Tatlonghari AU - Irene Thomas AU - Jane Rogers AU - Makoto Kobayashi AU - Jody Vykoukal AU - Jeannelyn Santiano Estrella AU - Sinchita Roy-Chowdhuri AU - Guangchun Han AU - Shaojun Zhang AU - Xizeng Mao AU - Xingzhi Song AU - Jianhua Zhang AU - Jian Gu AU - Randy L Johnson AU - George Adrian Calin AU - Guang Peng AU - Ju-Seog Lee AU - Samir M Hanash AU - Andrew Futreal AU - Zhenning Wang AU - Linghua Wang AU - Jaffer A Ajani Y1 - 2019/06/06 UR - http://gut.bmj.com/content/early/2019/06/06/gutjnl-2018-318070.abstract N2 - 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. ER -