Clinicopathologic characteristics and molecular features of BRG1-deficient non-small cell lung cancer (NSCLC).

12083 Background: Genomic alterations (GA) in SMARCA4, the gene encoding the SWI/SNF complex subunit BRG1, have been observed in 10% of NSCLC. RNA-based analyses suggest that loss of BRG1 expression is frequently associated with frameshift/nonsense (F/N) SMARCA4 GA. In preclinical studies, BRG1 deficiency sensitizes to enhancer zeste homolog 2 (EZH2) inhibition combined with chemotherapy (PMID: 25629630). To characterize the subset with SMARCA4 GA, we reviewed 2 independent NSCLC datasets and analyzed BRG1 protein expression in cases with available tissue. Methods: To identify cases with SMARCA4 GA, we examined the molecular profiles of 27,281 NSCLCs sequenced at Foundation Medicine (FM) and a separate cohort of 820 consecutive NSCLCs sequenced at Massachusetts General Hospital (MGH). We performed immunohistochemistry (IHC) using the Abcam rabbit BRG1 antibody (EPR3912) to assess BRG1 expression in NSCLCs with SMARCA4 GA. Results: We detected SMARCA4 GA in 73 (9%) and 3,188 (11%) patients (pts) in the MGH and FM datasets, respectively. SMARCA4 GA were distributed throughout all protein domains. F/N GA comprised approximately one-third of SMARCA4 GA in both groups (MGH: 32% and FM:36%). 40 pts (15 with F/N GA) in the MGH group had available tissue for IHC. Thirteen specimens—all from smokers with F/N SMARCA4 GA— had loss of BRG1 expression. Median age of pts with absent BRG1 expression was 69.2 years. Loss of BRG1 expression was observed in 9 adenocarcinomas as well as 2 poorly-differentiated,1 sarcomatoid, and 1 neuroendocrine carcinoma(s). Ten of the 13 pts with BRG1-deficient NSCLC underwent PD-L1 testing. Eight tumors had no PD-L1 expression and one had ≥50% expression. With the exception of 5 (38%) pts with concurrent KRAS GA, we did not find driver GA in the BRG1-deficient specimens. As BRG1 loss was limited to F/N GA, we queried the FM dataset to identify genes frequently co-altered with F/N SMARCA4 GA. F/N SMARCA4 GA commonly co-occurred with TP53 (74%), CDKN2A (38%), STK11 (34%), and KRAS (26%) GA. Conclusions: SMARCA4 GA are present in approximately 10% of NSCLC, but our data suggest that F/N GA may disproportionately lead to BRG1 loss. F/N SMARCA4 GA occur in 3-4% of NSCLC and overlap with KRAS GA.