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