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

Leora Witkowski, Jian Carrot-Zhang, Steffen Albrecht, Somayyeh Fahiminiya, Nancy Hamel, Eva Tomiak, David Grynspan, Emmanouil Saloustros, Javad Nadaf, Barbara Rivera, Catherine Gilpin, Ester Castellsagué, Rachel Silva-Smith, François Plourde, Mona Wu, Avi Saskin, Madeleine Arseneault, Rouzan G. Karabakhtsian, Elizabeth A. Reilly, Frederick R. UelandAnna Margiolaki, Kitty Pavlakis, Sharon M. Castellino, Janez Lamovec, Helen J. Mackay, Lawrence M. Roth, Thomas M. Ulbright, Tracey A. Bender, Vassilis Georgoulias, Michel Longy, Andrew Berchuck, Marc Tischkowitz, Inga Nagel, Reiner Siebert, Colin J.R. Stewart, Jocelyne Arseneau, W. Glenn McCluggage, Blaise A. Clarke, Yasser Riazalhosseini, Martin Hasselblatt, Jacek Majewski, William D. Foulkes

Research output: Contribution to journalArticlepeer-review

320 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)438-443
Number of pages6
JournalNature Genetics
Issue number5
StatePublished - May 2014

ASJC Scopus subject areas

  • Genetics


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