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.
Subject(s)
Stomach Neoplasms , Transcription Factors , Humans , Transcription Factors/genetics , Transcription Factors/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/therapy , Stomach Neoplasms/pathology , Nuclear Proteins/genetics , Epigenomics , Mutation , Tumor Microenvironment/genetics , DNA-Binding Proteins/genetics , Cell Cycle Proteins/geneticsABSTRACT
BACKGROUND: Primary repair or resection with anastomosis (PR/A) has been gaining increasing recognition for traumatic colonic injuries, with the need for faecal diversion (FD) especially those of penetrating etiology being questioned. However, the role of PR/A in critically ill patients is still controversial with concerns pertaining to safety and anastomotic leak. AIMS AND METHODS: We performed a systemic review of studies comparing outcomes of FD versus PR/A in traumatic colonic injuries. A systematic review was performed as per PRISMA guidelines utilizing three electronic databases: Pubmed, EMBASE, and Cochrane Library resources. Mortality and anastomotic leak rates are identified as the primary and secondary outcomes, respectively. Data extracted include mortality rates, type of surgical intervention, surgical complications, and need for DC (damage control) surgery. RESULTS: Fourteen studies were identified comprising 11 retrospective, 2 prospective cohort and 1 randomized trial with a total of 2071 patients. Six studies included patients that underwent DC surgery. The overall mortality rate was 3.77% and was higher in the FD group compared to PR/A group (5.38% vs 2.49%, p = 0.07). 71.3% of patients underwent PR/A with an overall leak rate of 4.63%. There was no difference in intra-abdominal collections between the PR/A and FD groups. In the subgroup analysis, anastomotic leak rate was significantly higher in the DC group compared to non-DC group (16.7% vs 3.2%, p = 0.003). CONCLUSIONS: This meta-analysis supports PR/A in stable patients with traumatic colonic injuries. FD should be considered in critically ill patients who require DC surgery as leak rates are significantly higher.
