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  • Comprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities

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Original research
Comprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities
  1. Chang Xu1,
  2. Kie Kyon Huang1,
  3. Jia Hao Law2,
  4. Joy Shijia Chua3,
  5. Taotao Sheng4,
  6. Natasha M Flores5,
  7. Melissa Pool Pizzi6,
  8. Atsushi Okabe7,
  9. Angie Lay Keng Tan1,
  10. Feng Zhu3,
  11. Vikrant Kumar1,
  12. Xiaoyin Lu5,
  13. Ana Morales Benitez5,
  14. Benedict Shi Xiang Lian1,
  15. Haoran Ma1,
  16. Shamaine Wei Ting Ho4,
  17. Kalpana Ramnarayanan1,
  18. Chukwuemeka George Anene-Nzelu8,9,10,11,
  19. Milad Razavi-Mohseni12,
  20. Siti Aishah Binte Abdul Ghani1,
  21. Su Ting Tay1,
  22. Xuewen Ong1,
  23. Ming Hui Lee1,
  24. Yu Amanda Guo13,
  25. Hassan Ashktorab14,
  26. Duane Smoot15,
  27. Shang Li1,16,
  28. Anders Jacobsen Skanderup13,
  29. Michael A Beer12,
  30. Roger Sik Yin Foo8,9,
  31. Joel Shi Hao Wong17,
  32. Kaushal Sanghvi17,
  33. Wei Peng Yong18,19,
  34. Raghav Sundar1,3,20,21,22,
  35. Atsushi Kaneda7,
  36. Shyam Prabhakar13,
  37. Pawel Karol Mazur5,
  38. Jaffer A Ajani6,
  39. Khay Guan Yeoh3,22,23,
  40. Jimmy Bok-Yan So2,22,24,
  41. Patrick Tan1,4,16,19,22,25,26
  42. Singapore Gastric Cancer Consortium
  1. 1Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
  2. 2Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  3. 3Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  4. 4Epigenetic and Epigenomic Regulation, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore
  5. 5Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  6. 6Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  7. 7Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
  8. 8Cardiovascular Research Institute, National University Health System, Singapore
  9. 9Human Genetics, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore
  10. 10Montreal Heart Institute, Quebec, Québec, Canada
  11. 11Department of Medicine, University of Montreal, Quebec, Québec, Canada
  12. 12Department of Biomedical Engineering and McKusick-Nathans Department of Genetic Medicine, Baltimore, Maryland, USA
  13. 13Computational and Systems Biology, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore
  14. 14Department of Medicine, Howard University, Washington, DC, USA
  15. 15Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee, USA
  16. 16Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  17. 17Department of General Surgery, Tan Tock Seng Hospital, Singapore
  18. 18Department of Haematology-Oncology, National University Health System, Singapore
  19. 19Cancer Science Institute of Singapore, National University of Singapore, Singapore
  20. 20Department of Haematology-Oncology, National University Cancer Institute, Singapore
  21. 21The N.1 Institute for Health, National University of Singapore, Singapore
  22. 22Singapore Gastric Cancer Consortium, Singapore
  23. 23Department of Gastroenterology and Hepatology, National University Health System, Singapore
  24. 24Division of Surgical Oncology, National University Cancer Institute, Singapore
  25. 25SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore
  26. 26Cellular and Molecular Research, National Cancer Centre, Singapore
  1. Correspondence to Dr Patrick Tan, Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore; gmstanp{at}duke-nus.edu.sg; Dr Jimmy Bok-Yan So, Department of Surgery, National University of Singapore, Singapore, Singapore; sursbyj{at}nus.edu.sg; Dr Chang Xu, Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore; chang.xu{at}duke-nus.edu.sg

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.

  • 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.

https://doi.org/10.1136/gutjnl-2022-328332

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    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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    Footnotes

    • 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.

    • 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.