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

Sohrab P Shah, Martin Köbel, Janine Senz, Ryan D Morin, Blaise A Clarke, Kimberly C Wiegand, Gillian Leung, Abdalnasser Zayed, Erika Mehl, Steve E Kalloger, Mark Sun, Ryan Giuliany, Erika Yorida, Steven Jones, Richard Varhol, Kenneth D Swenerton, Dianne Miller, Philip B Clement, Colleen Crane, Jason Madore, Diane Provencher, Peter Leung, Anna DeFazio, Jaswinder Khattra, Gulisa Turashvili, Yongjun Zhao, Thomas Zeng, J N Mark Glover, Barbara Vanderhyden, Chengquan Zhao, Christine A Parkinson, Mercedes Jimenez-Linan, David D L Bowtell, Anne-Marie Mes-Masson, James D Brenton, Samuel A Aparicio, Niki Boyd, Martin Hirst, C Blake Gilks, Marco Marra, David G Huntsman, The New England journal of medicine 360, 2719-29 (2009)


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.