@article {Wanggutjnl-2018-318070, author = {Ruiping Wang and Shumei Song and Kazuto Harada and Fatemeh Ghazanfari Amlashi and Brian Badgwell and Melissa Pool Pizzi and Yan Xu and Wei Zhao and Xiaochuan Dong and Jiangkang Jin and Ying Wang and Ailing Scott and Lang Ma and Longfei Huo and Diego Vicente and Mariela Blum Murphy and Namita Shanbhag and Ghia Tatlonghari and Irene Thomas and Jane Rogers and Makoto Kobayashi and Jody Vykoukal and Jeannelyn Santiano Estrella and Sinchita Roy-Chowdhuri and Guangchun Han and Shaojun Zhang and Xizeng Mao and Xingzhi Song and Jianhua Zhang and Jian Gu and Randy L Johnson and George Adrian Calin and Guang Peng and Ju-Seog Lee and Samir M Hanash and Andrew Futreal and Zhenning Wang and Linghua Wang and Jaffer A Ajani}, title = {Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response}, elocation-id = {gutjnl-2018-318070}, year = {2019}, doi = {10.1136/gutjnl-2018-318070}, publisher = {BMJ Publishing Group}, 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{\textquoteright}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 {\textquoteleft}clock-like{\textquoteright} 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: {\textquoteleft}mesenchymal-like{\textquoteright} and {\textquoteleft}epithelial-like{\textquoteright} with discriminating response to chemotherapy (31\% vs 71\%). Patients with the less responsive {\textquoteleft}mesenchymal-like{\textquoteright} 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.}, issn = {0017-5749}, URL = {https://gut.bmj.com/content/early/2019/06/06/gutjnl-2018-318070}, eprint = {https://gut.bmj.com/content/early/2019/06/06/gutjnl-2018-318070.full.pdf}, journal = {Gut} }