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    Mutation of FOXL2 in granulosa-cell tumors of the ovary

    Access Status
    Fulltext not available
    Authors
    Shah, S.
    Köbel, M.
    Senz, J.
    Morin, R.
    Clarke, B.
    Wiegand, K.
    Leung, G.
    Zayed, A.
    Mehl, E.
    Kalloger, S.
    Sun, M.
    Giuliany, R.
    Yorida, E.
    Jones, S.
    Varhol, Richard
    Swenerton, K.
    Miller, D.
    Clement, P.
    Crane, C.
    Madore, J.
    Provencher, D.
    Leung, P.
    DeFazio, A.
    Khattra, J.
    Turashvili, G.
    Zhao, Y.
    Zeng, T.
    Glover, J.
    Vanderhyden, B.
    Zhao, C.
    Parkinson, C.
    Jimenez-Linan, M.
    Bowtell, D.
    Mes-Masson, A.
    Brenton, J.
    Aparicio, S.
    Boyd, N.
    Hirst, M.
    Gilks, C.
    Marra, M.
    Huntsman, D.
    Date
    2009
    Type
    Journal Article
    
    Metadata
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    Citation
    Shah, S. and Köbel, M. and Senz, J. and Morin, R. and Clarke, B. and Wiegand, K. and Leung, G. et al. 2009. Mutation of FOXL2 in granulosa-cell tumors of the ovary. New England Journal of Medicine. 360 (26): pp. 2719-2729.
    Source Title
    New England Journal of Medicine
    DOI
    10.1056/NEJMoa0902542
    ISSN
    0028-4793
    School
    Department of Health Policy and Management
    URI
    http://hdl.handle.net/20.500.11937/31863
    Collection
    • Curtin Research Publications
    Abstract

    BACKGROUND: Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The pathogenesis of these tumors is unknown. Moreover, their histopathological diagnosis can be challenging, and there is no curative treatment beyond surgery. METHODS: We analyzed four adult-type GCTs using whole-transcriptome paired-end RNA sequencing. We identified putative GCT-specific mutations that were present in at least three of these samples but were absent from the transcriptomes of 11 epithelial ovarian tumors, published human genomes, and databases of single-nucleotide polymorphisms. We confirmed these variants by direct sequencing of complementary DNA and genomic DNA. We then analyzed additional tumors and matched normal genomic DNA, using a combination of direct sequencing, analyses of restriction-fragment-length polymorphisms, and TaqMan assays. RESULTS: All four index GCTs had a missense point mutation, 402C?G (C134W), in FOXL2, a gene encoding a transcription factor known to be critical for granulosa-cell development. The FOXL2 mutation was present in 86 of 89 additional adult-type GCTs (97%), in 3 of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%). The mutation was absent in 49 SCSTs of other types and in 329 unrelated ovarian or breast tumors. CONCLUSIONS: Whole-transcriptome sequencing of four GCTs identified a single, recurrent somatic mutation (402C?G) in FOXL2 that was present in almost all morphologically identified adult-type GCTs. Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs. Copyright © 2009 Massachusetts Medical Society. All rights reserved.

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