Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities. Issue 2 (11th July 2022)

• Record Type: Journal Article
• Authors: Ho, Shamaine Wei Ting; Sheng, Taotao; Xing, Manjie; Ooi, Wen Fong; Xu, Chang; Sundar, Raghav; Huang, Kie Kyon; Li, Zhimei; Kumar, Vikrant; Ramnarayanan, Kalpana; Zhu, Feng; Srivastava, Supriya; Isa, Zul Fazreen Bin Adam; Anene-Nzelu, Chukwuemeka George; Razavi-Mohseni, Milad; Shigaki, Dustin; Ma, Haoran; Tan, Angie Lay Keng; Ong, Xuewen; Lee, Ming Hui; Tay, Su Ting; Guo, Yu Amanda; Huang, Weitai; Li, Shang; Beer, Michael A.; Foo, Roger Sik Yin; Teh, Ming; Skanderup, Anders Jacobsen; Teh, Bin Tean; Tan, Patrick
• Is Part Of: Gut. Volume 72:Issue 2(2023)
• Page Start: 226
• Page End: 241
• Publication Date: 2022-07-11
• Subjects: gastric cancer; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2021-326483
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: Gastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities. Design: Transcriptomic profiles of ~1000 primary GCs and cell lines were analysed to derive a consensus Mes-GC classifier. Clinical and genomic associations were performed across >1200 patients with GC. Genome-wide epigenomic profiles (H3K27ac, H3K4me1 and assay for transposase-accessible chromatin with sequencing (ATAC-seq)) of 49 primary GCs and GC cell lines were generated to identify Mes-GC-specific enhancer landscapes. Upstream regulators and downstream targets of Mes-GC enhancers were interrogated using chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays and pharmacological inhibition. Results: We identified and validated a 993-gene cancer-cell intrinsic Mes-GC classifier applicable to retrospective cohorts or prospective single samples. Multicohort analysis of Mes-GCs confirmed associations with poor patient survival, therapy resistance and few targetable genomic alterations. Analysis of enhancer profiles revealed a distinctive Mes-GC epigenomic landscape, with TEAD1 as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. Analysis of Mes-GC super-enhancers also highlighted NUAK1 kinase as a downstream target, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment. Conclusion: Our results establish a consensus Mes-GC classifier applicable to multiple transcriptomic scenarios. Mes-GCs exhibit a distinct epigenomic landscape, and TEAD1 inhibition and combinatorial NUAK1 inhibition/cisplatin may represent potential targetable options.