P35.02 Lung Adenocarcinoma with Oncogenic SMARCA4 Mutation: Possible Target of Cancer Immunotherapy

Abstract

SWI/SNF complex, responsible for the transcriptional regulation through chromatin remodeling, is known to be altered in several malignancies. SMARCA4 gene, encoding a subunit of SWI/SNF complex, has been mutated in a subset of malignancies and its alteration may confer sensitivities to the several anti-neoplastic agents in preclinical model. However, the clinical and genomic characteristics of SMARCA4 gene-mutant lung adenocarcinoma have not been fully characterized. We investigated the proportions of SMARCA4 gene mutation both in lung adenocarcinoma cases in Asan Medical Center clinical next-generation sequencing cohort (AMC-LUAD) (n=249) and TCGA-LUAD (N=510) cohorts. The cases in the cohorts were divided into SMARCA4-likely oncogenic (SMARCA4-LO), SMARCA4-unknown and SMARCA4-wild type (SMARCA4-WT) groups according to the presence of SMARCA4 mutation and its oncogenic potential, and their clinicopathologic and mutational characteristics were compared. Differential gene expression (DEG) analysis between the three groups was performed using RNA-seq expression profile in TCGA-LUAD dataset. SMARCA4 gene mutation was identified in 25 (10%) and 43 (8.4%) cases and, of these, 15 (6.0%) and 24 (4.7%) cases were classified as SMARCA4-LO group in in AMC-LUAD and TCGA-LUAD cohorts, respectively. There were significant male and smoker predominance of SMARCA4-mutated groups in AMC-LUAD cohort (92.0% each), but these tendencies were non-significant in TCGA-LUAD cohort (60.5% and 76.7%, respectively). Large proportion of SMARCA4-LO group exhibited solid-predominant histologic features both in AMC-LUAD (13 of 15 cases; 87%) and TCGA-LUAD cohorts (19 of 24 cases; 79%). No concurrent driver gene alteration was not found in SMARCA4-LO group of AMC-LUAD cohort; however, oncogenic KRAS (3 cases), BRAF (1 case) and MAP2K1 (1 case) mutations were accompanied in a subset of SMARCA4-LO group of TCGA-LUAD cohort. The tumor mutation burden (TMB) of SMARCA4-LO group was significantly increased compared to that of the SMARCA4-WT patients both in AMC-LUAD and TCGA-LUAD cohorts (P<0.0001 each), and the case with high TMB (>10 mutations/Mb) was also frequent in SMARCA4-LO group of both cohorts (AMC-LUAD, P=0.0003; TCGA-LUAD, P=0.001). DEG analysis between SMARCA4-LO and SMARCA4-WT groups in TCGA-LUAD revealed significant upregulation of cancer-testis antigen genes and downregulation of lineage-specific genes in SMARCA4-LO group. Oncogenic SMARCA4 mutation may be identified in about 5% of lung adenocarcinoma and strongly associated with solid-predominant histologic pattern. The case with oncogenic SMARCA4 mutation may show high TMB and cancer-testis antigen expression, which serve as a target of immune checkpoint inhibitor therapy and cancer vaccine treatment.