Mutation of FOXL2 in granulosa-cell tumors of the ovary.

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. 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. 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. 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 SP ，Köbel M ，Senz J ，Morin RD ，Clarke BA ，Wiegand KC ，Leung G ，Zayed A ，Mehl E ，Kalloger SE ，Sun M ，Giuliany R ，Yorida E ，Jones S ，Varhol R ，Swenerton KD ，Miller D ，Clement PB ，Crane C ，Madore J ，Provencher D ，Leung P ，DeFazio A ，Khattra J ，Turashvili G ，Zhao Y ，Zeng T ，Glover JN ，Vanderhyden B ，Zhao C ，Parkinson CA ，Jimenez-Linan M ，Bowtell DD ，Mes-Masson AM ，Brenton JD ，Aparicio SA ，Boyd N ，Hirst M ，Gilks CB ，Marra M ，Huntsman DG ... -  《-》

Mutational analysis of FOXL2 codon 134 in granulosa cell tumour of ovary and other human cancers.

Kim MS ，Hur SY ，Yoo NJ ，Lee SH ... -  《-》

FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary.

Al-Agha OM ，Huwait HF ，Chow C ，Yang W ，Senz J ，Kalloger SE ，Huntsman DG ，Young RH ，Gilks CB ... -  《-》

Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W).

Kim JH ，Yoon S ，Park M ，Park HO ，Ko JJ ，Lee K ，Bae J ... -  《-》

Mutational analysis (c.402C>G) of the FOXL2 gene and immunohistochemical expression of the FOXL2 protein in testicular adult type granulosa cell tumors and incompletely differentiated sex cord stromal tumors.

Hes O ，Vaněček T ，Petersson F ，Grossmann P ，Hora M ，Perez Montiel DM ，Steiner P ，Dvořák M ，Michal M ... -  《-》