| Literature DB >> 24658002 |
Leora Witkowski1, Jian Carrot-Zhang2, Steffen Albrecht3, Somayyeh Fahiminiya4, Nancy Hamel5, Eva Tomiak6, David Grynspan7, Emmanouil Saloustros8, Javad Nadaf4, Barbara Rivera9, Catherine Gilpin6, Ester Castellsagué9, Rachel Silva-Smith10, François Plourde10, Mona Wu9, Avi Saskin11, Madeleine Arseneault4, Rouzan G Karabakhtsian12, Elizabeth A Reilly13, Frederick R Ueland13, Anna Margiolaki8, Kitty Pavlakis14, Sharon M Castellino15, Janez Lamovec16, Helen J Mackay17, Lawrence M Roth18, Thomas M Ulbright18, Tracey A Bender18, Vassilis Georgoulias8, Michel Longy19, Andrew Berchuck20, Marc Tischkowitz21, Inga Nagel22, Reiner Siebert22, Colin J R Stewart23, Jocelyne Arseneau24, W Glenn McCluggage25, Blaise A Clarke26, Yasser Riazalhosseini4, Martin Hasselblatt27, Jacek Majewski4, William D Foulkes28.
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.Entities:
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Year: 2014 PMID： 24658002 DOI： 10.1038/ng.2931
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330