The Pathognomonic FOXL2 C134W Mutation Alters DNA-Binding Specificity

The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumors (AGCT) and a diagnostic marker for this tumor type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore these mechanisms, we engineered V5-FOXL2(WT)- and V5-FOXL2(C134W)-inducible isogenic cell lines and performed chromatin immunoprecipitation sequencing and transcriptome profiling. FOXL2(C134W) associated with the majority of the FOXL2 wild-type DNA elements as well as a large collection of unique elements genome wide. This model enabled confirmation of altered DNA-binding specificity for FOXL2(C134W) and identification of unique targets of FOXL2(C134W) including SLC35F2, whose expression increased sensitivity to YM155. Our results suggest FOXL2(C134W) drives AGCT by altering the binding affinity of FOXL2-containing complexes to engage an oncogenic transcriptional program. Significance: A mechanistic understanding of FOXL2(C134W)-induced regulatory state alterations drives discovery of a rationally designed therapeutic strategy.