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.
- cancer genetics
- gastric cancer
- gastrointestinal cancer
- gene expression
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RW, SS and KH contributed equally.
Contributors SS, LW and JAA conceived and jointly supervised the study. RW conducted the major bioinformatics and biostatistics analysis of the multiplatform data, generated figures and tables for the manuscript. JZ, XS and XM contributed to raw WES data processing. GH and SZ assisted with WES and RNA-seq analysis. BB, MM, FGA, SC and JE assisted with clinical samples consent, collection and pathological evaluation. KH took charge of ascites cells isolations, DNA/RNA extraction and coordinated with DNA core facility for WES and RNA-seq and gathered all patients’ clinical information. YX, MP, JJ, YW, AS, LM, LH, NS, MK, JV, JG, PG, J-SL and ZW assisted and coordinated for tissues and ascites cells processing and other related analyses and experiments. LW, RW, SS, KH and JA wrote the manuscript. LW, JAA, RW, SS, KH, GZ, SH, ZW and AF revised the manuscript.
Funding This study was supported in part by the National Cancer Institute awards CA129906, CA127672, CA138671 and CA172741 and the DOD grants: CA150334 and CA162445 to JAA and DOD grants CA160433 and CA170906 to SS, and the start-up research funds provided to LW by the Department of Genomic Medicine, Division of Cancer Medicine of MD Anderson Cancer Center. This study was also supported by SMF Core grant CA016672 (SMF).
Competing interests None declared.
Ethics approval This project was approved by the institutional review committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All WES and RNA-Seq data have been deposited at the European Genome-phenome Archive (EGA). The datasets can be fully accessed under the accession number EGAS00001003180. Further information about EGA can be found on https://ega-archive.org (’the EGA of human data consented for biomedical research': http://www.nature.com/ng/journal/v47/n7/full/ng.3312.html).
Author note Reprints and permissions information is available at www.nature.com/reprints. Correspondence and requests for materials should be addressed to JA (firstname.lastname@example.org), SS (email@example.com) or LW (firstname.lastname@example.org).
Patient consent for publication Not required.
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