FOXL2 and Beyond: Unraveling Transcriptional Drivers in Ovarian Granulosa Cell Tumors

Background: Ovarian granulosa cell tumors (GCTs) are rare, hormonally active tumors that account for a significant portion of sex cord-stromal tumors. While FOXL2 mutations have been identified as a critical factor in adult-type GCTs, the broader transcriptional drivers involved in tumorigenesis remain poorly understood. Objective: This study aims to investigate the role of FOXL2 mutations and other transcriptional drivers such as WT1and SOX9 in the development and progression of ovarian granulosa cell tumors, and to assess their association with clinical outcomes. Methods: A prospective cohort study was conducted eastern region from January 2025 to augest 2025, involving 220 patients diagnosed with ovarian granulosa cell tumors. The study utilized genomic sequencing, RNA sequencing, and immunohistochemistry to analyze FOXL2 mutations, WT1, and SOX9 expression levels. Clinical data including tumor stage, treatment response, survival, and recurrence rates were also collected and analyzed. Results: FOXL2 mutations were present in 90% of adult-type GCTs, with FOXL2-positive tumors showing significantly better progression-free survival (48.5±11.3 months) and overall survival (55.2±10.5 months) compared to FOXL2-negative tumors (PFS = 30.1±8.7 months, OS = 41.3±7.9 months). WT1 and SOX9 expression were lower in FOXL2-positive tumors, suggesting a regulatory role of FOXL2 in tumor differentiation and progression. FOXL2-negative tumors were associated with advanced stages and higher recurrence rates (31.8%). Conclusion: FOXL2 mutations play a pivotal role in granulosa cell tumor pathogenesis, with FOXL2-positive tumorsshowing more favorable clinical outcomes. The study also identifies WT1 and SOX9 as important transcriptional drivers. These findings suggest that FOXL2 mutations can serve as diagnostic markers and prognostic indicators, and that targeted therapies addressing FOXL2 and related pathways may improve patient outcomes.