Abstract 2965: Identification of SMARCA4/BRG1 mutation types in NSCLC cell lines and tumors

Abstract

Abstract Purpose: Identification of SMARCA4/BRG1 mutation types in NSCLC cell lines and tumors. Background: The SMARCA4 gene encodes the major catalytic subunit of the SWI/SNF chromatin remodeling complex and is necessary for the transcriptional regulation of multiple cellular pathways. SMARCA4 is frequently mutated in lung cancer cell lines and in lung cancers. Methods: Sixty four NSCLC cell lines were analyzed. The Cancer Genome Atlas (TCGA) data were examined. SMARCA4 mutations were identified by NextGen and/or Sanger sequencing using genomic DNA or cDNA. Gene expression profiles and global methylation was determined by Illumina BeadChips. BRG1 protein was detected by immunoblotting. Results: SMARCA4 abnormalities were divided into Type1 (loss of full length protein, usually due to deletions, non-sense mutations or splicing site mutations) and Type 2 (homozygous or heterozygous missense mutations with protein present). Sequencing often failed to detect large deletions. Loss of SMARCA4/BRG1 resulted in profound downstream effects on the transcriptome and methylome, while existence of BRG1 with mutations has much less effects. Analysis using most significantly regulated transcripts can distinguish SMARCA4 type 1 abnormality from WT group, and indicate that type 2 abnormality effects were heterogeneous. SMARCA4 regulated transcripts are involved in many important cellular functions such as cell movement, death and proliferation and participate in many cytokines and hormone/nuclear receptors-mediated pathways. The expressions of transcription factors FOXA2 and NKX2-1 were decreased, while two groups of cancer testis antigens (CTAs), PRAME and MAGEA family were elevated in NSCLC cell lines and tumors with SMARCA4 mutations/low expression. Furthermore, FOXA2 and NKX2-1 were downregulated in an inducible SMARCA4 knock- down immortalized human lung epithelial cell line. Conclusions: SMARCA4 mutations can be divided into two types having varying downstream effects. Citation Format: Wei Zhang, Yibing Yao, Yunyun Zhou, Xiaotu Ma, Jingsheng Yan, Tao Wang, Luc Girard, John Minna, Guanghua Xiao, Yang Xie, Adi Gazdar. Identification of SMARCA4/BRG1 mutation types in NSCLC cell lines and tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2965. doi:10.1158/1538-7445.AM2015-2965