Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and understudied cancer with a dismal prognosis. SCCOHT's infrequency has hindered empirical study of its biology and clinical management. However, we and others have recently identified inactivating mutations in the SWI/SNF chromatin remodeling gene SMARCA4 with concomitant loss of SMARCA4 protein in the majority of SCCOHT tumors.1–4 Here we summarize these findings and report SMARCA4 status by targeted sequencing and/or immunohistochemistry (IHC) in an additional 12 SCCOHT tumors, 3 matched germlines, and the cell line SCCOHT-1. We also report the identification of a homozygous inactivating mutation in the gene SMARCB1 in one SCCOHT tumor with wild-type SMARCA4, suggesting that SMARCB1 inactivation may also play a role in the pathogenesis of SCCOHT. To date, SMARCA4 mutations and protein loss have been reported in the majority of 69 SCCOHT cases (including 2 cell lines). These data firmly establish SMARCA4 as a tumor suppressor whose loss promotes the development of SCCOHT, setting the stage for rapid advancement in the biological understanding, diagnosis, and treatment of this rare tumor type.

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

“…It has been reported that SCCOHT shares similarities with malignant rhabdoid tumors (MRT) despite having mutations in different SWI/SNF complex members (20,21,27). The molecular, histopathological, and clinical commonalities between SCCOHT and rhabdoid tumors have led to the suggestion that SCCOHT be reclassified as "malignant rhabdoid tumor of the ovary" (MRTO) (20,27).…”

“…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.…”

“…Most SCCOHT patients receive a combination of surgery and multiagent chemotherapy, but the large majority either do not respond or rapidly relapse following treatment with available therapies; hence, the one-year overall survival rate for SCCOHT patients is only 50%. Interestingly, SCCOHT tumors share many similarities with rhabdoid tumors (20,21,27,28). They are both aggressive forms of cancer that respond poorly to conventional therapy.…”

Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities

“…SMARCA4 and SMARCA2 are mammalian homologs of the SNF2-like ATPases in yeast and Drosophila, which use ATP hydrolysis to power the remodeling activity of CRCs [20]. SMARCA4 protein inactivation or loss-of-function point mutations [21] have been reported across neoplasms of various tissue types, including the lung [22–25], blood (Burkitt lymphoma) [21,26], brain (pediatric medulloblastoma) [21,27], ovary [28,29], pancreas [30], and others. Whether this specific intra-complex synthetic lethal relationship between paralog subunits holds true across a wide range of cancer types remains to be determined.…”

“…Over the past two years, sequencing studies of solid tumors revealed that two tumor types, small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and SMARCA4-deficient thoracic sarcomas (SMARCA4-DTS) feature genetic loss of SMARCA4 [28,76–79] with concomitant silencing of SMARCA2. Immunohistochemical staining of SCCOHT tumor samples showed reduced or absent nuclear SMARCA2 protein [79], indicating that not all cancers that feature loss of SMARCA4 will benefit from a SMARCA2 ATPase inhibitor.…”