FOXL2 Mutation Associated With Adult Ovarian Granulosa Cell Tumors

Maurie Markman, MD


November 11, 2009

Mutation in FOXL2 in Granulosa-Cell Tumors of the Ovary

Shah SP, Kobel M, Senz J, et al
N Engl J Med. 2009;360:2719-2729. Epub 2009 Jun 10


Investigators exploring the genetic profile of a small number of adult ovarian granulosa cell tumors found that each had a specific missense point mutation in FOXL2 (402C > G [C134W]), a gene that had previously been shown to play an important role in the normal development of ovarian granulosa cells. To validate their findings, they examined 89 additional adult ovarian granulosa cell tumors and found that 86 (97%) had the same missense mutation. Of note, the FOXL2 mutation was not seen in the 329 ovarian or breast cancers examined, nor in 49 nongranulosa cell malignant ovarian sex cord-stromal tumors, but was seen in 1 of 10 ovarian juvenile-type granulosa cell tumors as well as in 3 of 14 thecomas.


Adult ovarian granulosa cell tumors are uncommon, representing only 5% of all gynecologic malignancies. Fortunately, the majority of patients with this entity present with early-stage disease and are cured with surgical resection. However, in the setting of metastatic or recurrent cancer, treatment options are quite limited and of marginal effectiveness. The finding of a single, highly specific mutation in essentially all patients with adult granulosa cell tumors leads to the intriguing hypothesis that the presence of this abnormality is the direct cause of the condition and that its expression may be required for the survival or progression of the malignant cell population. Efforts to develop safe and effective inhibitors of the function of FOXL2, or strategies designed to restore the wild-type phenotype, may have important therapeutic implications in women with advanced granulosa cell cancers.



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