Intratumoral heterogeneity and loss of ARID1A expression in gastric cancer correlates with increased PD-L1 expression in Western patients

Abstract

Recent whole-genome sequencing showed frequent mutations of ARID1A in gastric cancer (GC). In this study of a large independent Central European cohort, we evaluated the expression of ARID1A in whole tissue sections (WTS) of GC testing the following hypotheses: ARID1A shows intratumoral heterogeneity, and ARID1A expression and/or heterogeneity correlates with clinicopathological patient characteristics. ARID1A expression was studied by immunohistochemistry in 450 primary GCs and 143 corresponding lymph node metastases. The expression pattern was correlated with clinicopathological characteristics and patient survival. ARID1A genotype and CpG methylation status were additionally analyzed in 7 GCs with a heterogeneous "black-and-white" expression pattern. ARID1A was expressed heterogeneously in 23 (5.1%) GCs, depicting a black-and-white pattern of negative and positive tumor areas. Complete loss of expression was found in 43 (9.6%) GCs. ARID1A status correlated significantly with tumor type according to Laurén, Epstein-Barr virus status, microsatellite instability, PD-L1 status, and nodal spread. There was no correlation with patient survival. In 4 cases with heterogeneous ARID1A expression, frame shift variants were detected. Summing up, heterogeneous or complete loss of ARID1A expression occurred in 14.7% of GCs and correlated with PD-L1 status, indicating potential for future combined anti-PD-L1/ARID1A therapy. In a subgroup of cases, ARID1A loss was heterogeneous, which suggests that ARID1A mutations might be a later event in gastric carcinogenesis.