Mutation of FOXL2 in Granulosa-Cell Tumors of the Ovary

作者：Sohrab P. Shah, Martin Köbel, Janine Senz, Ryan D. Morin, Blaise Alexander Clarke, Kimberly C. Wiegand, Gillian Leung, Abdalnasser Zayed, Erika Mehl, Steve E. Kalloger, Mark Sun, Ryan Giuliany, Erika Yorida, Steven J.M. Jones, Richard Varhol, Kenneth D. Swenerton, Dianne M. Miller, Philip B. Clement, Colleen A. Crane, Jason Madore, Diane Michele Provencher, Peter C. K. Leung, Anna DeFazio, Jaswinder Khattra, Gulisa Turashvili, Yongjun Zhao, Thomas Zeng, J. N. Mark Glover, Barbara C. Vanderhyden, Chengquan Zhao, Christine Parkinson, Mercedes Jimenez‐Liñan, David D.L. Bowtell, Anne‐Marie Mes‐Masson, James D. Brenton, Samuel A. J. R. Aparicio, Niki Boyd, Martin Hirst, C. Blake Gilks, Marco A. Marra, David George Huntsman · 发表于：New England Journal of Medicine · 年份：2009 · DOI：10.1056/nejmoa0902542 · 被引用次数：780 · 研究领域：Ovarian cancer diagnosis and treatment、Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities、Testicular diseases and treatments

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 adul...