Somatic ARID1A mutation stratifies patients with gastric cancer to PD-1 blockade and adjuvant chemotherapy

Abstract

Background AT-rich interaction domain 1A (ARID1A) encodes a vital component of switch/sucrose non-fermentable chromatin-remodeling complex. Given its association with genomic instability, we conducted this study to determine whether ARID1A mutation status had an impact on therapeutic responsiveness in gastric cancer (GC), especially combinatory chemo-immunotherapy. Methods We retrospectively enrolled a total of 1162 patients from five independent cohorts. ZSHS Cohort and TCGA Cohort were designed to inform chemotherapeutic relevance and immunobiology of ARID1A-mutant GC based on tissue samples and sequencing data, respectively. MSKCC Cohort, mGC Cohort, and Melanoma Cohort were utilized to interrogate the predictive efficacy of ARID1A mutation to programmed cell death protein 1 (PD-1) blockade. Results ARID1A mutation was enriched in EBV-positive, hypermutated-single nucleotide variant and microsatellite-unstable subtype GC, and was predictive of responsiveness to both fluorouracil-based chemotherapy and PD-1 blockade. Specifically, ARID1A mutation score was a highly sensitive indicator (91%) of response to pembrolizumab. Mechanistically, ARID1A mutation correlated with extensive DNA damage repair deficiency and immunogenic tumor microenvironment (TME) featured by elevated activated subsets of CD8+ T cells, CD4+ T cells, and NK cells. Type 17T helper cells were typically abundant in ARID1A-mutant GC and might be a precondition for chemosensitivity conferred by ARID1A mutation. Furthermore, ARID1A mutation indicated elevated expression of VEGFA and CLDN18, as well as over-representation of ERBB2 and FGFR2 signaling pathway. Conclusions ARID1A-mutant GC displayed immunogenic TME and might be a candidate for both monotherapy and the combination of frontline chemotherapy and PD-1 blockade.

Clinical outcome and molecular landscape of patients with ARID1A‐loss gastric cancer

“…Our previous investigation has documented ARID1A-mutant GC as a molecularly distinct subtype exhibiting an immunogenic TME and a wide spectrum of therapeutic targets. 16 Nevertheless, we have also detected the presence of background noise arising from haploid functionality. In fact, apart from somatic mutations, DNA…”

“…Immunohistochemistry staining for ARID1A and ARID1A expression evaluation were carried out according to previous protocols 16 . For the TCGA, SMC, and ZSHS immunotherapy cohorts, ARID1A ‐loss GC was defined as patients with ARID1A mutation (missense mutation, nonsense mutation, frame shift deletion, frame shift insert, splice site) or copy number deletion (hemizygous deletion or homozygous deletion).…”

“…Immunohistochemistry staining for ARID1A and ARID1A expression evaluation were carried out according to previous protocols. 16 For…”

“…15 In GC, our previous study revealed that somatic ARID1A mutation could predict superior response to fluorouracil-based adjuvant chemotherapy (ACT) and anti-PD1 immunotherapy. 16 However, due to the presence of haploinsufficiency, ARID1A loss of function could also be a result of copy number deletion. 17,18 This indicated that GC patients with either ARID1A point mutation or copy number deletion might refer to the same entity.…”

Prognostic Significance of Cuproptosis-Related Gene Signatures in Breast Cancer Based on Transcriptomic Data Analysis

“…Cancer has been widely considered to be the result of the accumulation of genetic mutations, including the gain of function of oncogenes and loss of function of tumor suppressors [ 38 , 39 , 40 ]. We analyzed 15 common somatic gene mutation rates between the high-risk and low-risk subgroups and found significant differences in P53 and PIK3CA mutations, with the high-risk group being positively associated with a PIK3CA mutation and the low-risk group being positively associated with a p53 mutation.…”