Article Text
PDF
Abstract
Objective Gastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities.
Design Transcriptomic profiles of ~1000 primary GCs and cell lines were analysed to derive a consensus Mes-GC classifier. Clinical and genomic associations were performed across >1200 patients with GC. Genome-wide epigenomic profiles (H3K27ac, H3K4me1 and assay for transposase-accessible chromatin with sequencing (ATAC-seq)) of 49 primary GCs and GC cell lines were generated to identify Mes-GC-specific enhancer landscapes. Upstream regulators and downstream targets of Mes-GC enhancers were interrogated using chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays and pharmacological inhibition.
Results We identified and validated a 993-gene cancer-cell intrinsic Mes-GC classifier applicable to retrospective cohorts or prospective single samples. Multicohort analysis of Mes-GCs confirmed associations with poor patient survival, therapy resistance and few targetable genomic alterations. Analysis of enhancer profiles revealed a distinctive Mes-GC epigenomic landscape, with TEAD1 as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. Analysis of Mes-GC super-enhancers also highlighted NUAK1 kinase as a downstream target, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment.
Conclusion Our results establish a consensus Mes-GC classifier applicable to multiple transcriptomic scenarios. Mes-GCs exhibit a distinct epigenomic landscape, and TEAD1 inhibition and combinatorial NUAK1 inhibition/cisplatin may represent potential targetable options.
- gastric cancer
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Statistics from Altmetric.com
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Footnotes
SWTH and TS contributed equally.
Contributors SWTH, TS and PT conceptualised and designed the study, and wrote and revised the manuscript. SWTH, MX, CX, ZL, KR, ZFBAI, CGA-N and XO performed the experiments. SWTH, TS, WFO, RS, KKH, VK, MR-M, DS, HM, YAG, WH and MAB analysed the data. FZ, SS, ALKT, XO, MHL, STT, SL, RSYF, MT, AJS and BTT provided facilities, reagents and/or intellectual input. PT supervised the study.
Funding This work was supported by National Medical Research Council grants NMRC/STaR/0026/2015, MOH‐OFLCG18May0003 and MOH‐000967 (MOH‐STaR21jun‐0001) and A*STAR IAF-PP grant H20H6a0030. Funding was also provided by the Cancer Science Institute of Singapore, NUS, under the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative, and block funding was provided by Duke-NUS Medical School.
Competing interests PT has stock and other ownership interests in Tempus Healthcare, previous research funding from Kyowa Hakko Kirin and Thermo Fisher Scientific, and patents/other intellectual property through the Agency for Science and Technology Research, Singapore (all outside the submitted work). RS has received honoraria from MSD, Eli Lilly, Bristol Myers Squibb, Roche, Taiho, Astra Zeneca and DKSH; has advisory activity with Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD and GSK; received research funding from MSD and Paxman Coolers; and has received travel grants from Astra Zeneca, Eisai, Roche, Taiho and DKSH. All remaining authors have declared no conflicts of interest.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.