Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type

Abstract

Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high‐grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4‐negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re‐expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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

“…Interestingly, a study showed that the histone deacetylase inhibitor trichostatin A was able to reactivate the expression of SMARCA2 in a SMARCA2-low SCCOHT cell line. The same study showed that reexpression of either ATPase in SCCOHT cell lines was able to inhibit cell growth emphasizing the importance of SMARCA2 and SMARCA4 dual loss in SCCOHT (24). We also observed upregulation of SMARCA2 upon tazemetostat treatment in SCCOHT cell lines (Fig.…”

“…Interestingly, these lines do not have any described coding mutations in SMARCA2, suggesting that the mechanism of SMARCA2 inactivation is possibly through epigenetic silencing, as has been described previously to occur in SCCOHT and other indications (23,24). As dual loss of SMARCA2 and SMARCA4 has been recently demonstrated to be a defining characteristic of SCCOHT within ovarian cancer (23,24), these observations highly suggest that TOV112D, OVK18, and COV434 cell lines are derived from SCCOHT tumors that were misdiagnosed as a different ovarian cancer subtype. Interestingly, granulosa cell tumors, from which COV434 was derived, are categorized as a form of ovarian cancer that is known to mimic SCCOHT morphologically (36).…”

“…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. SMARCA4 activity is lost via genomic mutations, whereas SMARCA2 mRNA is lost in the absence of any coding mutations (19)(20)(21)(22)(23)(24). Increasing evidence now suggests that the dual loss of SMARCA2 and SMARCA4 is a molecular signature and defining feature of SCCOHT.…”

“…Increasing evidence now suggests that the dual loss of SMARCA2 and SMARCA4 is a molecular signature and defining feature of SCCOHT. Reexpression of either ATPase in SCCOHT cell lines have been shown to inhibit cell growth emphasizing the importance of SMARCA2 and SMARCA4 dual loss in SCCOHT (24). SCCOHT is a rare and lethal subtype of ovarian cancer that mainly affects adolescent and young adult women (25,26).…”

Diagnostic immunohistochemistry in gynaecological neoplasia: a brief survey of the most common scenarios

“…Morphologically, SCC-HT is reminiscent of small cell lung carcinoma and present hyperchromatic, ungrooved nuclei, with frequent mitoses. Recently, it has been shown that SMARCA4 is specifically mutated in over 90% of SCC-HT, and this genetic aberration produces a loss of SMARCA4 (BRG1) protein expression37 that can be used as a valid adjunct in the differential diagnosis of SCC-HT.…”