The role of FOXL2 in the pathogenesis of adult ovarian granulosa cell tumours.

Abstract: Objective: It has been four years since the discovery of the FOXL2 402C>G mutation in adult ovarian granulosa cell tumours. Yet to date, there have been few studies which have investigated the precise role of the mutation in tumour pathogenesis. This review aims to summarise the research in this area, proposes a mechanism of action for the mutation, and explores the implications for clinical practice and future therapeutics. Methods: A literature search was performed with the keywords ‘granulosa cell tumour’ and ‘FOXL2’ on PubMed. Results: Although the search returned 52 articles, of these only nine publications investigate the pathogenic effect of the mutant FOXL2 allele. Mutant FOXL2 maintains some of the transcriptional activity of the wildtype allele, but there is a subtle alteration of the expression in a unique suite of cancer-related genes. The mutation appears to deregulate the anti-proliferative transforming growth factor beta (TGF-β) pathway and this may contribute to the pathogenesis of adult GCTs. The inability of mutant FOXL2 to elicit an effective apoptotic signalling cascade may also be important in GCT pathogenesis. Conclusion: The 402C>G mutation in FOXL2 is central to the development of adult granulosa cell tumours. Based on the evidence, we suggest that FOXL2 is an oncogene or tumour suppressor depending on the genetic context that is the GCT subtype. [Copyright &y& Elsevier]