TY - JOUR
T1 - Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type
AU - Witkowski, Leora
AU - Carrot-Zhang, Jian
AU - Albrecht, Steffen
AU - Fahiminiya, Somayyeh
AU - Hamel, Nancy
AU - Tomiak, Eva
AU - Grynspan, David
AU - Saloustros, Emmanouil
AU - Nadaf, Javad
AU - Rivera, Barbara
AU - Gilpin, Catherine
AU - Castellsagué, Ester
AU - Silva-Smith, Rachel
AU - Plourde, François
AU - Wu, Mona
AU - Saskin, Avi
AU - Arseneault, Madeleine
AU - Karabakhtsian, Rouzan G.
AU - Reilly, Elizabeth A.
AU - Ueland, Frederick R.
AU - Margiolaki, Anna
AU - Pavlakis, Kitty
AU - Castellino, Sharon M.
AU - Lamovec, Janez
AU - Mackay, Helen J.
AU - Roth, Lawrence M.
AU - Ulbright, Thomas M.
AU - Bender, Tracey A.
AU - Georgoulias, Vassilis
AU - Longy, Michel
AU - Berchuck, Andrew
AU - Tischkowitz, Marc
AU - Nagel, Inga
AU - Siebert, Reiner
AU - Stewart, Colin J.R.
AU - Arseneau, Jocelyne
AU - McCluggage, W. Glenn
AU - Clarke, Blaise A.
AU - Riazalhosseini, Yasser
AU - Hasselblatt, Martin
AU - Majewski, Jacek
AU - Foulkes, William D.
N1 - Funding Information:
This work is dedicated to the memory of Georgia Enter and Latosha Durham. We thank K. Hill and the Small Cell Ovarian Cancer Foundation for help in recruitment to this study, B. Vanderhyden (University of Ottawa) for providing the BIN-67 cells, S. Croce and C.S. Choong for aiding in the collection of pathological samples, P.-O. Fiset for help with immunohistochemistry and N. Benlimame, R. Zühlke-Jenisch, C. Kemming, M. Leiße, S. Peetz-Dienhart, L. Raestrup, K. Schmidt and C. Theile for technical assistance. N. Jabado, I. Bah and members of the Foulkes laboratory provided helpful discussions. We also thank the McGill University and Génome Québec Innovation Centre for their cooperation, H. Pierce for her help with contacting family 1 and D. Samelak for her help with family 3. Equipment for immunohistochemistry analysis was made available through Sonderforschungsbereich Transregio (SFB TR) 128 (grant to T. Kuhlmann (Z1)). We received funding from the Jewish General Hospital Foundation and the Jodi Taiger Lazarus Fund (W.D.F.), the Fonds de Recherche du Québec–Santé (L.W.), KinderKrebsInitiative Buchholz/Holm-Seppensen (R.S.) and Interdisziplinären Zentrum für Klinische Forschung (IZKF) Münster (Ha3/016/11) (M.H.).
PY - 2014/5
Y1 - 2014/5
N2 - 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.
AB - 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.
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U2 - 10.1038/ng.2931
DO - 10.1038/ng.2931
M3 - Article
C2 - 24658002
AN - SCOPUS:84899644463
SN - 1061-4036
VL - 46
SP - 438
EP - 443
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -