High expression of SMARCA4 or SMARCA2 is frequently associated with an opposite prognosis in cancer

Abstract

The gene encoding the ATPase of the chromatin remodeling SWI/SNF complexes SMARCA4 (BRG1) is often mutated or silenced in tumors, suggesting a role as tumor suppressor. Nonetheless, recent reports show requirement of SMARCA4 for tumor cells growth. Here, we performed a computational meta-analysis using gene expression, prognosis, and clinicopathological data to clarify the role of SMARCA4 and the alternative SWI/SNF ATPase SMARCA2 (BRM) in cancer. We show that while the SMARCA4 gene is mostly overexpressed in tumors, SMARCA2 is almost invariably downexpressed in tumors. High SMARCA4 expression was associated with poor prognosis in many types of tumors, including liver hepatocellular carcinoma (LIHC), and kidney renal clear cell carcinoma (KIRC). In contrast, high SMARCA2 expression was associated with good prognosis. We compared tumors with high versus low expression of SMARCA4 or SMARCA2 in LIHC and KIRC cohorts from The Cancer Genome Atlas. While a high expression of SMARCA4 is associated with aggressive tumors, a high expression of SMARCA2 is associated with benign differentiated tumors, suggesting that SMARCA4 and SMARCA2 play opposite roles in cancer. Our results demonstrate that expression of SMARCA4 and SMARCA2 have a high prognostic value and challenge the broadly accepted general role of SMARCA4 as a tumor suppressor.

Novel Interactions between the Human T-Cell Leukemia Virus Type 1 Antisense Protein HBZ and the SWI/SNF Chromatin Remodeling Family: Implications for Viral Life Cycle

“…This analysis indicates that BRG1 was abundantly expressed in HTLV-1-positive cell lines and ATL cell lines, compared to the HTLV-2-positive cell line or an uninfected cell line. Even though the number of HTLV-infected cell lines tested is small, these findings appear compatible with previous reports showing that BRG1 is overexpressed in different cancer types, such as gastric carcinomas (53), liver hepatocellular carcinoma (HCC), kidney renal clear cell carcinoma, and breast cancer (45,54).…”

“…Here, we have illustrated that BRG1 is highly expressed in HTLV-1-infected cell lines and ATL cell lines, suggesting that elevated BRG1 expression may contribute to the phenotype of these cells. Our findings appear compatible with previously reported evidence showing that BRG1 is overexpressed in other cancer types, including, but not limited to, gastric carcinomas (53), liver hepatocellular carcinoma (HCC), kidney renal clear cell carcinoma, and breast cancer (45,54). Several studies have presented that BRG1 is required for tumor cell proliferation.…”

BRG1 is a prognostic indicator and a potential therapeutic target for prostate cancer

“…Although the TCGA data set did not contain information on BRM protein levels, a prior report revealed that BRM protein levels did not correlate with increased BRG1 protein in patient samples (49). A recent survey of multiple tumor types indicated that BRG1 expression was elevated in tumors whereas BRM was not (56).…”

Dramatic increase in gene mutational burden after transformation of follicular lymphoma into TdT+ B-lymphoblastic leukemia/lymphoma

“…Given the additional aspect of "dedifferentiation" implied by this lymphoblastic transformation, mutations that affect these epigenetic pathways may be of particular importance in this context. Intriguingly, one of the two other published cases of a similar transformation in which WES was performed showed likely loss of function of both KMT2D and SMARCA2, a related protein to SMARCA4, albeit with unique features (Slot et al 2016;Guerrero-Martínez and Reyes 2018). This may represent an overlapping mechanism in these transformations.…”

“…Another mutation of interest in this case is SMARCA4 A948T. SMARCA4 has a known role in cancer and has been typically considered a tumor suppressor gene, although there has been some recent debate of the exact role it plays in malignant cells (Chakravarty et al 2017;Guerrero-Martínez and Reyes 2018). SMARCA4 functions in a SWI/SNF complex, regulating chromatin remodeling to control gene expression, perhaps requiring KDM6A (Miller et al 2010).…”