학술논문
Comprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities
Document Type
Article
Author
Xu, Chang; Huang, Kie Kyon; Law, Jia Hao; Chua, Joy Shijia; Sheng, Taotao; Flores, Natasha M; Pizzi, Melissa Pool; Okabe, Atsushi; Tan, Angie Lay Keng; Zhu, Feng; Kumar, Vikrant; Lu, Xiaoyin; Benitez, Ana Morales; Lian, Benedict Shi Xiang; Ma, Haoran; Ho, Shamaine Wei Ting; Ramnarayanan, Kalpana; Anene-Nzelu, Chukwuemeka George; Razavi-Mohseni, Milad; Abdul Ghani, Siti Aishah Binte; Tay, Su Ting; Ong, Xuewen; Lee, Ming Hui; Guo, Yu Amanda; Ashktorab, Hassan; Smoot, Duane; Li, Shang; Skanderup, Anders Jacobsen; Beer, Michael A; Foo, Roger Sik Yin; Wong, Joel Shi Hao; Sanghvi, Kaushal; Yong, Wei Peng; Sundar, Raghav; Kaneda, Atsushi; Prabhakar, Shyam; Mazur, Pawel Karol; Ajani, Jaffer A; Yeoh, Khay Guan; So, Jimmy Bok-Yan; Tan, Patrick
Source
Gut; 2023, Vol. 72 Issue: 9 p1651-1663, 13p
Subject
Language
ISSN
00175749; 14683288
Abstract
ObjectiveGastric cancer (GC) is a leading cause of cancer mortality, with ARID1Abeing the second most frequently mutated driver gene in GC. We sought to decipher ARID1A-specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1Aloss.DesignGenomic profiling of GC patients including a Singapore cohort (>200 patients) was performed to derive mutational signatures of ARID1Ainactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A-mutated GCs were analysed to examine tumour microenvironmental changes arising from ARID1Aloss. 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.ResultsWe observed prevalent ARID1Ainactivation 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 NFKB1and 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.ConclusionOur results suggest a therapeutic strategy for ARID1A-mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes.