Objective Gastric cancer (GC) is a leading cause of cancer mortality, with ARID1A being the second most frequently mutated driver gene in GC. We sought to decipher ARID1A-specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1A loss.
Design Genomic profiling of GC patients including a Singapore cohort (>200 patients) was performed to derive mutational signatures of ARID1A inactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A-mutated GCs were analysed to examine tumour microenvironmental changes arising from ARID1A loss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks of ARID1A-mutated GCs were converged at the genomic, single-cell and epigenomic level, and targeted by pharmacological inhibition.
Results We observed prevalent ARID1A inactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven proinflammatory tumour microenvironment. ARID1A-depletion caused loss of H3K27ac activation signals at ARID1A-occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such as NFKB1 and NFKB2. Promoter activation in ARID1A-mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific to ARID1A-genomic status.
Conclusion Our results suggest a therapeutic strategy for ARID1A-mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes.
- gastric cancer
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.Data are available upon reasonable request. Please contact Prof Patrick Tan.
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CX and KKH contributed equally.
Contributors Conceptualisation: CX, KKH, JB-YS and PT; data acquisition and curation: CX, JHL, JSC, NMF, MPP, ALKT, FZ, XL, AMB, BSXL, KR, CGA-N, SABAG, STT, RSYF, JSHW, KS, WPY, RS, PKM, JAA and KGY; formal analysis: CX, KKH, TS, AO, VK, HM, SWTH, MR-M, MAB and AK; facilities, reagents and intellectual support: XO, MHL, YAG, HA, DS, SL and AJS; funding acquisition: SP and PT; visualisation: CX, KKH, TS, VK and HM; writing of the original draft: CX and KKH; writing (review and editing): JB-YS and PT; guarantor: PT.
Funding This work was supported by National Medical Research Council grants NMRC/ STaR/0026/2015, and National Medical Research Council grant MOH-000967-00 (MOH-STaR21jun-0001) for P.T. K.K.H. was supported by a Khoo Postdoctoral Fellowship. This research was also supported by the National Research Foundation, Singapore, and Singapore Ministry of Health’s National Medical Research Council under its Open Fund-Large Collaborative Grant (“OF-LCG”) (MOH-OFLCG18May-0003). This work was also supported by SCISSOR (A*STAR IAF-PP) grant H18/01/a0/020 funded by Biomedical Research Council, Agency for Science, Technology and Research. This research was supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative, and block funding from Duke-NUS Medical School and Genome Institute of Singapore.
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 Bristol-Myers Squibb, Lilly, Roche, Taiho, Astra Zeneca, DKSH and MSD; has advisory activity with Bristol-Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD and AstraZeneca; received research funding from MSD and Paxman Coolers; and has received travel grants from AstraZeneca, Eisai, Roche and Taiho Pharmaceutical.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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