TY - JOUR
T1 - Comprehensive molecular phenotyping of ARID1A -deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities
AU - Xu, Chang
AU - Huang, Kie Kyon
AU - Law, Jia Hao
AU - Chua, Joy Shijia
AU - Sheng, Taotao
AU - Flores, Natasha M.
AU - Pizzi, Melissa Pool
AU - Okabe, Atsushi
AU - Tan, Angie Lay Keng
AU - Zhu, Feng
AU - Kumar, Vikrant
AU - Lu, Xiaoyin
AU - Benitez, Ana Morales
AU - Lian, Benedict Shi Xiang
AU - Ma, Haoran
AU - Ho, Shamaine Wei Ting
AU - Ramnarayanan, Kalpana
AU - Anene-Nzelu, Chukwuemeka George
AU - Razavi-Mohseni, Milad
AU - Abdul Ghani, Siti Aishah Binte
AU - Tay, Su Ting
AU - Ong, Xuewen
AU - Lee, Ming Hui
AU - Guo, Yu Amanda
AU - Ashktorab, Hassan
AU - Smoot, Duane
AU - Li, Shang
AU - Skanderup, Anders Jacobsen
AU - Beer, Michael A.
AU - Foo, Roger Sik Yin
AU - Wong, Joel Shi Hao
AU - Sanghvi, Kaushal
AU - Yong, Wei Peng
AU - Sundar, Raghav
AU - Kaneda, Atsushi
AU - Prabhakar, Shyam
AU - Mazur, Pawel Karol
AU - Ajani, Jaffer A.
AU - Yeoh, Khay Guan
AU - So, Jimmy Bok Yan
AU - Tan, Patrick
N1 - Publisher Copyright:
© 2023 BMJ Publishing Group. All rights reserved.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - 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.
AB - 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.
KW - gastric cancer
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U2 - 10.1136/gutjnl-2022-328332
DO - 10.1136/gutjnl-2022-328332
M3 - Article
C2 - 36918265
AN - SCOPUS:85152700828
SN - 0017-5749
VL - 72
SP - 1651
EP - 1663
JO - Gut
JF - Gut
IS - 9
ER -