The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors

Adult-type granulosa cell tumors (AGCT) are the most common type of malignant ovarian sex cord-stromal tumors. Most AGCTs carry the somatic variant c.402C>G (p.C134W) affecting the tran-scription factor FOXL2. Germline dominant variants in FOXL2 are responsible for blepharophimosis syndrome, which is characterized by underdevelopment of the eyelid. In this work, we generated a mouse model harboring the C134W variant of FOXL2 to evaluate in vivo the poorly understood oncogenic role of FOXL2. The mutation was dominant regarding eyelid hypoplasia, reminiscent of blepharophimosis syndrome. Interestingly, Foxl2 thorn /C134W female mice had reduced fertility and developed AGCTs through a pro-gression from abnormal ovaries with aberrant granulosa cells to ovaries with stromal hyperplasia and atypia and on to tumors in adut mice. The genes dysregulated in mouse AGCTs exhibited the hallmarks of cancer and were consistent with a gain-of-function of the mutated allele affecting TGFI3 signaling. A com-parison of these data with previous results on human AGCTs indicated similar deregulated pathways. Finally, a mutational anal-ysis of mouse AGCT transcriptomic data suggested the absence of additional driver mutations apart from FOXL2-C134W. These results provide a clear in vivo example in which a single mutational hit triggers tumor development associated with profound transcrip-tomic alterations. Significance: A newly generated mouse model carrying a FOXL2 mutation characteristic of adult-type granulosa cell tumors shows that FOXL2 C134W shifts the transcriptome towards a signature of granulosa cell cancer and drives tumorigenesis.

Automated summary

This study utilized a mouse model carrying a FOXL2 gene mutation to demonstrate that FOXL2 C134W mutation is associated with the development of malignant ovarian tumors, and the analysis of transcriptomic data suggests that FOXL2-C134W is the only driver mutation for tumor development.