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Published at www.nejm.org June 10, 2009 (10.1056/NEJMoa0902542)

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ABSTRACT

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, 402CG (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 (402CG) 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.

Source Information

The authors' affiliations are listed in the Appendix.

This article (10.1056/NEJMoa0902542) was published on June 10, 2009, at NEJM.org.

Address reprint requests to Dr. Huntsman at the Center for Translational and Applied Genomics, British Columbia Cancer Agency, 600 W. 10th Ave., Vancouver, BC V5Z 4E6, Canada, or at dhuntsma{at}bccancer.bc.ca.

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