Xu C, Huang KK, Law JH, Chua JS, Sheng T, Flores NM, Pizzi MP, Okabe A, Tan ALK, Zhu F, Kumar V, Lu X, Benitez AM, Lian BSX, Ma H, Ho SWT, Ramnarayanan K, Anene-Nzelu CG, Razavi-Mohseni M, Abdul Ghani SAB, Tay ST, Ong X, Lee MH, Guo YA, Ashktorab H, Smoot D, Li S, Skanderup AJ, Beer MA, Foo RSY, Wong JSH, Sanghvi K, Yong WP, Sundar R, Kaneda A, Prabhakar S, Mazur PK, Ajani JA, Yeoh KG, So JB, Tan P.
Affiliations
- 1Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore gmstanp@duke-nus.edu.sg sursbyj@nus.edu.sg chang.xu@duke-nus.edu.sg.
- 2Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
- 3Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
- 4Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
- 5Epigenetic and Epigenomic Regulation, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore.
- 6Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
- 7Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
- 8Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
- 9Cardiovascular Research Institute, National University Health System, Singapore.
- 10Human Genetics, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore.
- 11Montreal Heart Institute, Quebec, Québec, Canada.
- 12Department of Medicine, University of Montreal, Quebec, Québec, Canada.
- 13Department of Biomedical Engineering and McKusick-Nathans Department of Genetic Medicine, Baltimore, Maryland, USA.
- 14Computational and Systems Biology, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore.
- 15Department of Medicine, Howard University, Washington, DC, USA.
- 16Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee, USA.
- 17Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
- 18Department of General Surgery, Tan Tock Seng Hospital, Singapore.
- 19Department of Haematology-Oncology, National University Health System, Singapore.
- 20Cancer Science Institute of Singapore, National University of Singapore, Singapore.
- 21Department of Haematology-Oncology, National University Cancer Institute, Singapore.
- 22The N.1 Institute for Health, National University of Singapore, Singapore.
- 23Singapore Gastric Cancer Consortium, Singapore.
- 24Department of Gastroenterology and Hepatology, National University Health System, Singapore.
- 25Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore gmstanp@duke-nus.edu.sg sursbyj@nus.edu.sg chang.xu@duke-nus.edu.sg.
- 26Division of Surgical Oncology, National University Cancer Institute, Singapore.
- 27SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore.
- 28Cellular and Molecular Research, National Cancer Centre, Singapore.
Abstract
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.
PMID: 36918265 DOI: 10.1136/gutjnl-2022-328332