Lung cancer with loss of BRG1/BRM, shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features

Abstract

BRG1 and BRM, two core catalytic subunits in SWI ⁄ SNF chromatin remodeling complexes, have been suggested as tumor suppressors, yet their roles in carcinogenesis are unclear. Here, we present evidence that loss of BRG1 and BRM is involved in the progression of lung adenocarcinomas. Analysis of 15 lung cancer cell lines indicated that BRG1 mutations correlated with loss of BRG1 expression and that loss of BRG1 and BRM expression was frequent in E-cadherin-low and vimentin-high cell lines. Immunohistochemical analysis of 93 primary lung adenocarcinomas showed loss of BRG1 and BRM in 11 (12%) and 16 (17%) cases, respectively. Loss of expression of BRG1 and BRM was frequent in solid predominant adenocarcinomas and tumors with low thyroid transcription factor-1 (TTF-1, master regulator of lung) and low cytokeratin7 and E-cadherin (two markers for bronchial epithelial differentiation). Loss of BRG1 was correlated with the absence of lepidic growth patterns and was mutually exclusive of epidermal growth factor receptor (EGFR) mutations. In contrast, loss of BRM was found concomitant with lepidic growth patterns and EGFR mutations. Finally, we analyzed the publicly available dataset of 442 cases and found that loss of BRG1 and BRM was frequent in E-cadherin-low, TTF-1-low, and vimentin-high cases and correlated with poor prognosis. We conclude that loss of either or both BRG1 and BRM is involved in the progression of lung adenocarcinoma into solid predominant tumors with features of epithelial mesenchymal transition and loss of the bronchial epithelial phenotype. BRG1 loss was specifically involved in the progression of EGFR wild-type, but not EGFR-mutant tumors. (Cancer Sci 2013; 104: 266-273) L ung cancer is the leading cause of cancer death in many developed countries, including the United States and Japan. (1,2) The identification of genetic abnormalities, such as epidermal growth factor receptor (EGFR) mutations, KRAS mutations, EML4-ALK translocation, and MET amplifications has revolutionized our understanding of the molecular mechanisms in lung cancer development. (3) However, it has become increasingly apparent that epigenetic alternations play equally important roles in tumorigenesis, and among them, chromatin remodeling factors have attracted much attention recently. (4) Indeed, identification of mutations of chromatin remodeling factors in cancer has been a major hot topic in the past 2 years. (5)(6)(7)(8) BRG1 and BRM, two core catalytic ATPase subunits in human SWI ⁄ SNF chromatin remodeling enzymes, have now emerged as bona fide tumor suppressor genes. (9)(10)(11)(12) Inactivating mutations of BRG1 have been identified in 35% of non-small cell lung cancer cell lines and a subset of primary lung cancer. (9) In a mouse model of lung cancer, targeted knockout of BRG1 can affect tumor development. (10) In contrast to BRG1, mutations of BRM have rarely been identified and epigenetic silencing of BRM plays a contributory role in some cancers. (4,11) However, whether loss of BRG1 and BRM affects phenotype and...

Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

“…Cancer cells harboring BRG1 mutations are highly sensitive to BRM depletion, demonstrating a unique role for BRM containing complexes in promoting tumor cell growth. It is interesting to note, however, that a subpopulation of lung cancers with BRG1 mutations or BRG1 loss are reported to have low/no expression of BRM (13,14), suggesting that such cancers have alternate mechanisms that allow survival in the absence of both ATPases. Although it is not known how cancer cells that lose both ATPases survive, our data indicates that BRG1-deficient cancer cells expressing BRM remain highly sensitive to BRM inhibition.…”

“…Pointing to the broader relevance of mSWI/SNF complexes in cancers, mutations in the accessory subunits such as ARID1A/BAF250A have been reported in ovarian clear cell and endometrial carcinomas among others (9,10), and PBRM1/BAF180 in clear cell renal cell carcinomas (11). Mutations and/or loss of expression of the catalytic subunit BRG1 have been reported predominantly in nonsmall cell lung cancers (12)(13)(14)(15)(16), but also in others (2,17,18). In support of its tumor suppressor function, BRG1 reexpression inhibits the growth of BRG1-mutant/deficient cancer cell lines (19), and Brg1 heterozygous mice develop mammary carcinomas (20).…”

Loss of function of SWI/SNF chromatin remodeling genes leads to genome instability of human lung cancer

“…To elucidate this issue, we established a mutation reporter to evaluate the mutation ratio in a lung carcinoma cell line, Calu-3. SMARCA4, the most frequently mutated BAF gene in lung carcinoma (8,12,30), was used from loss of function assay in established mutation reporter. We confirmed that the SMARCA4 gene protected the genome against mutation occurrence, upon stable SMARCA4 in mutation reporter cells of lung carcinoma, consistent with its requirement during embryogenesis and its role as a tumor suppressor to maintain genome stability (31).…”

Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models

“…SMARCA4 and SMARCA2 are the two mutually exclusive ATPase catalytic subunits of the SWI/SNF complex that have postulated tumor suppressor roles in cancers such as non-small cell lung cancer (NSCLC; refs. 16,17). In addition, multiple reports indicate that the expression of SMARCA4 and SMARCA2 are concomitantly lost in a subset of NSCLC (16)(17)(18).…”

“…16,17). In addition, multiple reports indicate that the expression of SMARCA4 and SMARCA2 are concomitantly lost in a subset of NSCLC (16)(17)(18). Interestingly, in a rare type of ovarian cancer, small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), SMARCA4 and SMARCA2 have been found to be coinactivated.…”