Abstract 2179: Histopathologic and genetic features of lung adenocarcinomas with loss of chromatin remodeling factors, BRG-1 and BRM

Abstract

Abstract We have recently demonstrated that lung adenocarcinoma could be classified into two groups; Group1 is characterized by (1) high expressions of bronchial epithelial markers (TTF-1, MUC1, CK7, and E-cadherin), (2) high phosphorylation of EGFR and MET, (3) frequent mutation or amplification of EGFR, MET and HER2, (4) high expressions of the genes associated with invasion (HER3, MET, Cox-2, laminin β2), and (5) sensitivity to gefitinib and resistance to cisplatin; Group2 is characterized by negative expression of bronchial epithelial markers, no or a little phosphorylation of EGFR and MET, no mutation or amplification of EGFR, MET and HER2, low expressions of many of the genes associated with cancer invasion, and resistance to gefitinib and sensitivity to cisplatin (Matsubara et al, AJP 2010). The activations of receptor tyrosine kinase EGFR and MET would participate in the regulatory network of cancer-associated genes in Group 1. In contrast, rare genetic alterations of EGFR and MET in Group 2 suggest that this group of tumors might have different processes of carcinogenesis. BRG-1 and BRM are two core catalytic ATPase subunits in human SWI/SNF chromatin remodeling complexes, and they have been suggested as tumor suppressors. Now we aimed to reveal the histopathologic/genetic features of lung adenocarcinomas with loss of BRG1 and BRM. METHODS: We analyzed (1) the publicly available data set of 442 lung adenocarcinomas (Shedden et al, Nat Med 2008), and (2) 93 primary lung adenocarcinomas resected in our institution. For the latter set, we analzed the expression of BRG-1 and BRM by immunohistochemistry. RESULTS: Our analysis of the Shedden et al. data revealed that high expressions of BRG1 and BRM were frequently seen in cases with high expressions of bronchial epithelial markers, and that cases with loss of BRG1 or BRM showed significantly poorer prognosis. Among the 93 cases of lung adenocarcinoma in our institution, 11 showed BRG1 loss, and 13 showed BRM loss. BRG1 loss was significantly more frequent in the Group2 (70%) than the Group1 (7%) (p<0.0001), but no significant difference was seen in the frequency of BRM loss between the two groups; 13% in the Group1and 28% in the Group2. Most cases with BRG1 loss were heavy smokers and showed components of solid adenocarcinoma, but lacked lepidic growth pattern. In contrast, cases with BRM loss frequently showed both components of solid adenocarcinoma and adenocarcinoma with lepidic growth pattern. BRG1 loss and EGFR mutations were mutually exclusive, but EGFR mutations were found in about half of the cases with BRM loss. Conclusions: BRG1 loss occurs exclusively in EGFR wild-type tumors and tumors without lepidic growth pattern. BRG1 loss might be associated with carcinogenesis of the Group 2 tumors. In contrast, BRM loss might be involved in the progression of Group1 tumors from adenocarcinoma with lepidic growth into solid adenocarcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2179. doi:1538-7445.AM2012-2179