Prognostic and immune infiltration significance of ARID1A in TCGA molecular subtypes of gastric adenocarcinoma

Abstract

BackgroundAT‐rich interaction domain 1A (ARID1A) is an essential subunit of the switch/sucrose non‐fermentable chromatin remodeling complex and is considered to be a tumor suppressor. The Cancer Genome Atlas (TCGA) molecular classification has deepened our understanding of gastric cancer at the molecular level. This study explored the significance of ARID1A expression in TCGA subtypes of gastric adenocarcinoma.MethodsWe collected 1248 postoperative patients with gastric adenocarcinoma, constructed tissue microarrays, performed immunohistochemistry for ARID1A, and obtained correlations between ARID1A and clinicopathological variables. We then carried out the prognostic analysis of ARID1A in TCGA subtypes. Finally, we screened patients by random sampling and propensity score matching method and performed multiplex immunofluorescence to explore the effects of ARID1A on CD4, CD8, and PD‐L1 expression in TCGA subtypes.ResultsSeven variables independently associated with ARID1A were screened out: mismatch repair proteins, PD‐L1, T stage, differentiation status, p53, E‐cadherin, and EBER. The independent prognostic variables in the genomically stable (GS) subtype were N stage, M stage, T stage, chemotherapy, size, and ARID1A. PD‐L1 expression was higher in the ARID1A negative group than in the ARID1A positive group in all TCGA subgroups. CD4 showed higher expression in the ARID1A negative group in most subtypes, while CD8 did not show the difference in most subtypes. When ARID1A was negative, PD‐L1 expression was positively correlated with CD4/CD8 expression; while when ARID1A was positive, this correlation disappeared.ConclusionsThe negative expression of ARID1A occurred more frequently in the Epstein–Barr virus and microsatellite instability subtypes and was an independent adverse prognostic factor in the GS subtype. In the TCGA subtypes, ARID1A negative expression caused increased CD4 and PD‐L1 expression, whereas CD8 expression appeared independent of ARID1A. The expression of CD4/CD8 induced by ARID1A negativity was accompanied by an increase in PD‐L1 expression.

ARID1A Mutations in Gastric Cancer: A Review with Focus on Clinicopathological Features, Molecular Background and Diagnostic Interpretation

“…Notably, ARID1A mutations were predominantly found in the EBV-positive subtype, suggesting a specific pathway of disease development in this group [ 35 ]. Building upon this molecular landscape, in 2015, the ACRG reclassified gastric cancer into four distinct subtypes to better direct treatment and prognosis [ 57 , 58 ]. These subtypes are MSI, MSS/EMT, MSS/TP53+, and MSS/TP53−.…”

“…These subtypes are MSI, MSS/EMT, MSS/TP53+, and MSS/TP53−. The mutation rates of ARID1A in these subtypes were: 44.2% in MSI, 13.9% in MSS/EMT, 18.6% in MSS/TP53+, and 5.9% in MSS/TP53− [ 57 , 58 ]. In this scenario, recent studies have highlighted that the deletion and/or mutation of ARID1A increases the efficiency of EBV infection in gastric epithelial cells, linking genetic alterations in GC with viral infection, and suggesting potential novel avenues of therapeutic intervention [ 59 , 60 ].…”