Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T)

“…This suggests SDHD immunohistochemistry as a potential complementary tool to SDHB immunohistochemistry to identify SDHD-mutated patients. 62 Further adding to those rare familial cases characterized by disparity between molecular genetic aberrations of a tumor suppressor gene and retention of protein expression, 63 one papillary renal cell carcinomas arising in a patient with a germline missense SDHC mutation (c.3G4A p.M1I) and harboring somatic loss of heterozygosity of the SDHC locus paradoxically displayed SDHB immunopositivity. 36 Taken together, SDHB immunohistochemistry and SDH-x genetic analysis should be viewed as complementary tests.…”

Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome

“…Missense (and most often gain-of-function) mutations in SMARCB1 and SMARCA4 are most often associated with rare developmental syndromes, including CoffinSiris syndrome (43,44) and Nicolaides-Baraitser syndrome (45). However, missense SMARCB1 and SMARCA4 mutations have been identified in RTs and SCCOHT (31,46), and loss-offunction mutations have been seen in developmental disorders (47). Both missense and nonsense SMARCB1 mutations have been seen in schwannomatosis, but the nonsense mutations may be localized to specific regions of the gene and are thought to be hypomorphic loss of function (48).…”

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, 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.…”