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Background  Despite their distinct biology, granulosa cell tumours (GCTs) are treated the same as other ovarian tumours. Intriguingly, a recurring somatic mutation in the transcription factor Forkhead Box L2 ( FOXL2 ) 402C>G has been found in nearly all GCTs examined. This investigation aims to identify the pathogenicity of mutant  FOXL2  by studying its altered transcriptional targets.    Methods  The expression of mutant  FOXL2  was reduced in the GCT cell line KGN, and wildtype and mutant  FOXL2  were overexpressed in the GCT cell line COV434. Total RNA was hybridised to Affymetrix U133 Plus 2 microarrays. Comparisons were made between the transcriptomes of control cells and cells altered by  FOXL2  knockdown and overexpression, to detect potential transcriptional targets of mutant  FOXL2 .    Results  The overexpression of wildtype and mutant  FOXL2  in COV434, and the silencing of mutant  FOXL2  expression in KGN, has shown that mutant  FOXL2  is able to differentially regulate the expression of many genes, including two well known  FOXL2  targets,  StAR  and  CYP19A . We have shown that many of the genes regulated by mutant FOXL2 are clustered into functional annotations of cell death, proliferation, and tumourigenesis. Furthermore,  TGF-β  signalling was found to be enriched when using the gene annotation tools GATHER and GeneSetDB. This enrichment was still significant after performing a robust permutation analysis.    Conclusion  Given that many of the transcriptional targets of mutant  FOXL2  are known  TGF-β  signalling genes, we suggest that deregulation of this key antiproliferative pathway is one way mutant  FOXL2  contributes to the pathogenesis of adult-type GCTs. We believe this pathway should be a target for future therapeutic interventions, if outcomes for women with GCTs are to improve.

The Transcriptional Targets of Mutant FOXL2 in Granulosa Cell Tumours