Mutation of FOXL2 in Granulosa-Cell Tumors of the Ovary.

¹Centre for Translational and Applied Genomics of British Columbia Cancer Agency and the Provincial Health Services Authority Laboratories, Vancouver, BC, Canada

² Genetic Pathology Evaluation Centre of the Departments of Pathology of the  Vancouver General Hospital, British Columbia Cancer Agency and the University of British Columbia and the Prostate Research Centre, Vancouver BC, Canada.

³ Genome Sciences Centre, British Columbia Cancer Agency, Vancouver BC, Canada

⁴ Department of Pathology, University of Toronto and University Health Network, Toronto, Canada

⁵ Cheryl Brown Ovarian Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver, BC, Canada

⁶ Department of Gynecology, Vancouver General Hospital and British Columbia Cancer Agency, Vancouver BC, Canada,

⁷ Department of Pathology and Laboratory Medicine, University of Ottawa,   Ottawa,Canada

⁸ Centre de recherche du Centre hospitalier de l'Université de Montréal (CR-CHUM),  Montreal, Quebec, Canada

⁹ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver BC, Canada

¹⁰ Department of Gynaecological Oncology, Westmead Hospital and Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead NSW Australia

¹¹ Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver , British Columbia Canada

¹² Department of Biochemistry, University of Alberta, Edmonton, AB, Canada

¹³ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada

¹⁴ Department of Pathology, Magee-Women’s Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

¹⁵ Functional Genomics of Ovarian Cancer Laboratory, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK

The authors' affiliations are listed in the Appendix. This article (10.1056/NEJMoa0902542) was published on June 10, 2009, at NEJM.org.

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-transc riptome 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 transc riptomes 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 transc ription 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-transc riptome 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.