Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 360, Issue 26, Pages 2719-2729Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa0902542
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Funding
- British Columbia Cancer Foundation
- Vancouver General Hospital Foundation
- Genome Canada
- Michael Smith Foundation for Health Research
- Eli Lilly Canada
- Canadian Institutes of Health Research's Training Program on Clinician-Scientists in Molecular Oncologic Pathology
- Sanofi-Aventis
- OvCaRe and Ovarian Cancer Canada
- Fonds de la Recherche en Sante du Quebec (Montreal)
- Ovarian Cancer Canada (Ottawa)
- Australian National Health and Medical Research Council
- Cancer Research UK
- University of Cambridge, Hutchinson Whampoa
- Experimental Cancer Medicine Centre
- National Institute for Health Research's Cambridge Biomedical Research Centre
- U. S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- Cancer Council Tasmania
- Cancer Foundation of Western Australia
- National Health and Medical Research Council of Australia
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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.
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