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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Witkowski, L; Carrot-Zhang, J; Albrecht, S; Fahiminiya, S; Hamel, N; Tomiak, E; Grynspan, D; Saloustros, E; Nadaf, J; Rivera, B; Gilpin, C; Castellsagué, E; Silva-Smith, R; Plourde, F; Wu, M; Saskin, A; Arseneault, M; Karabakhtsian, RG; Reilly, EA; Ueland, FR; Margiolaki, A; Pavlakis, K; Castellino, SM; Lamovec, J; Mackay, HJ; Roth, LM; Ulbright, TM; Bender, TA; Georgoulias, V; Longy, M; Berchuck, A; Tischkowitz, M; Nagel, I; Siebert, R; Stewart, CJR; Arseneau, J; McCluggage, WG; Clarke, BA; Riazalhosseini, Y; Hasselblatt, M; Majewski, J; Foulkes, WD

Published Date

  • May 2014

Published In

Volume / Issue

  • 46 / 5

Start / End Page

  • 438 - 443

PubMed ID

  • 24658002

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/ng.2931


  • eng

Conference Location

  • United States