title: Mutation of FOXL2 in granulosa-cell tumors of the ovary.
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.
authors.affiliation: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: Sohrab P
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authors.lastname: Shah
authors.forename: Martin
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authors.lastname: Köbel
authors.forename: Janine
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authors.lastname: Senz
authors.forename: Ryan D
authors.initials: RD
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authors.forename: Blaise A
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authors.forename: Erika
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authors.lastname: Swenerton
authors.forename: Dianne
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authors.lastname: Miller
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authors.forename: Colleen
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authors.lastname: Crane
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authors.forename: Diane
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authors.lastname: Provencher
authors.forename: Peter
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authors.lastname: Leung
authors.forename: Anna
authors.initials: A
authors.lastname: DeFazio
authors.forename: Jaswinder
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authors.lastname: Khattra
authors.forename: Gulisa
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authors.lastname: Turashvili
authors.forename: Yongjun
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authors.lastname: Zhao
authors.forename: Thomas
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authors.lastname: Zeng
authors.forename: J N Mark
authors.initials: JN
authors.lastname: Glover
authors.forename: Barbara
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authors.lastname: Vanderhyden
authors.forename: Chengquan
authors.initials: C
authors.lastname: Zhao
authors.forename: Christine A
authors.initials: CA
authors.lastname: Parkinson
authors.forename: Mercedes
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authors.lastname: Jimenez-Linan
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Aparicio
authors.forename: Niki
authors.initials: N
authors.lastname: Boyd
authors.forename: Martin
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authors.lastname: Hirst
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: Marco
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mesh_terms: D001483:Base Sequence; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D005819:Genetic Markers; D005838:Genotype; D006106:Granulosa Cell Tumor / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D017423:Sequence Analysis, RNA; D019914:Taq Polymerase
chemical_list: C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D005819:Genetic Markers; D019914:Taq Polymerase