Περίληψη:
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. © 2014 Nature America, Inc. All rights reserved.
Συγγραφείς:
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, R.G.
Reilly, E.A.
Ueland, F.R.
Margiolaki, A.
Pavlakis, K.
Castellino, S.M.
Lamovec, J.
Mackay, H.J.
Roth, L.M.
Ulbright, T.M.
Bender, T.A.
Georgoulias, V.
Longy, M.
Berchuck, A.
Tischkowitz, M.
Nagel, I.
Siebert, R.
Stewart, C.J.R.
Arseneau, J.
McCluggage, W.G.
Clarke, B.A.
Riazalhosseini, Y.
Hasselblatt, M.
Majewski, J.
Foulkes, W.D.
Λέξεις-κλειδιά:
BRG1 protein; DNA; BRG1 protein, allele; article; cell line; chromatin assembly and disassembly; clinical article; controlled study; DNA sequence; exome; familial cancer; gene deletion; genetic counseling; germline mutation; human; hypercalcemia; immunohistochemistry; missense mutation; ovary carcinoma; priority journal; small cell carcinoma; small cell carcinoma of the ovary hypercalcemic type; somatic mutation; wild type; adolescent; adult; Article; child; female; frameshift mutation; gene expression; gene sequence; heterozygosity loss; human tissue; hypercalcemia; immunoreactivity; nonsense mediated mRNA decay; ovary carcinoma; RNA splicing; small cell carcinoma; small cell carcinoma of the ovary hypercalcemic type; stop codon, Base Sequence; Carcinoma, Small Cell; Cell Line, Tumor; DNA Helicases; Exome; Female; Gene Components; Humans; Immunoblotting; Immunohistochemistry; In Situ Hybridization, Fluorescence; Molecular Sequence Data; Mutation; Nuclear Proteins; Ovarian Neoplasms; Sequence Analysis, DNA; Transcription Factors
