ARID1A mutations and expression loss in non-small cell lung carcinomas: clinicopathologic and molecular analysis.

A subset of non-small cell lung carcinomas harbors mutations in ARID1A, a component of the SWI/SNF complex implicated in modulating response to immunotherapy in diverse tumors. This study characterized the spectrum of ARID1A mutations and expression by targeted sequencing and immunohistochemistry, respectively. In a consecutive series of 2440 non-small cell lung carcinomas, ARID1A mutations were present in 184 (7.5%), within which 69% harbored loss-of-function mutations. Of 139 ARID1A-mutated tumors available for immunohistochemistry, ARID1A expression was aberrant in 64 (46%), including diffuse complete loss in 13 (9%), diffuse diminished expression in 17 (12%), and heterogeneous loss with a geographic or interspersed pattern in 34 (25%). Complete loss of ARID1A expression correlated with ARID1A premature-truncating mutations with evidence of biallelic inactivation. Both ARID1A mutations and aberrant expression correlated with a lack of EGFR mutations, frequent TP53 mutations, and increased mutational burden. ARID1A-mutant tumors showed similar overall survival compared with ARID1A-wild-type tumors; however, among patients with ARID1A-mutant tumors, aberrant ARID1A expression correlated with worse overall survival. Lung tumors with diffuse loss of ARID1A expression were predominantly adenocarcinomas, poorly differentiated, almost exclusively from smokers, and enriched for mismatch repair deficiency. Geographic heterogeneous ARID1A loss was notable in three tumors, including an adenocarcinoma showing fetal-like differentiation in areas with ARID1A loss. Overall, loss of ARID1A expression at the protein level is seen in fewer than 2% of non-small cell lung carcinomas but is associated with distinct clinicopathologic features. Our findings suggest a need for caution in interpretation of the functional significance of ARID1A mutations from sequencing data.