Mutation of FOXL2 in granulosa-cell tumors of the ovary.
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.
Shah
Sohrab P
SP
Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, Canada.
Köbel
Martin
M
Senz
Janine
J
Morin
Ryan D
RD
Clarke
Blaise A
BA
Wiegand
Kimberly C
KC
Leung
Gillian
G
Zayed
Abdalnasser
A
Mehl
Erika
E
Kalloger
Steve E
SE
Sun
Mark
M
Giuliany
Ryan
R
Yorida
Erika
E
Jones
Steven
S
Varhol
Richard
R
Swenerton
Kenneth D
KD
Miller
Dianne
D
Clement
Philip B
PB
Crane
Colleen
C
Madore
Jason
J
Provencher
Diane
D
Leung
Peter
P
DeFazio
Anna
A
Khattra
Jaswinder
J
Turashvili
Gulisa
G
Zhao
Yongjun
Y
Zeng
Thomas
T
Glover
J N Mark
JN
Vanderhyden
Barbara
B
Zhao
Chengquan
C
Parkinson
Christine A
CA
Jimenez-Linan
Mercedes
M
Bowtell
David D L
DD
Mes-Masson
Anne-Marie
AM
Brenton
James D
JD
Aparicio
Samuel A
SA
Boyd
Niki
N
Hirst
Martin
M
Gilks
C Blake
CB
Marra
Marco
M
Huntsman
David G
DG
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
C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D005819:Genetic Markers; D019914:Taq Polymerase