FOXL2 – Adult-Type Ovarian Granulosa Cell Tumor

Adult-type ovarian granulosa cell tumors (aGCTs) are rare ovarian malignancies characterized by unpredictable late recurrence and malignant potential. Unlike juvenile granulosa cell tumors, aGCTs harbor a pathognomonic somatic hotspot mutation in the FOXL2 transcription factor gene, c.402C>G (p.Cys134Trp), which serves as a near-universal molecular marker of this disease ([PMID:21623383]).

Multiple cohort studies have established that the FOXL2 c.402C>G mutation occurs in the vast majority of aGCTs but is absent in juvenile forms. In a study of 34 adult and 20 juvenile tumors, 19/27 adult aGCTs (70%) carried the mutation, whereas 0/18 juvenile tumors were positive ([PMID:21623383]). A MALDI-TOF MS assay in an independent Israeli cohort detected FOXL2 c.402C>G in 18/20 aGCTs (90%) and confirmed its specificity over 95% in adult cases ([PMID:21640373]). A recent review reported that FOXL2 C134W defines nearly all sporadic aGCTs across cohorts ([PMID:27813081]).

In a representative case, an 80-year-old patient with an adult-type granulosa-theca cell tumor exhibited a heterozygous somatic FOXL2 c.402C>G mutation by direct sequencing; despite defective DNA mismatch repair, no recurrence was seen over 3 years, underscoring the role of FOXL2 alteration in tumor initiation but not necessarily progression ([PMID:25297715]).

Genetic evidence is based on a single recurrent somatic missense variant exclusively in tumor tissue. No germline segregation or familial cases have been reported, and FOXL2 c.402C>G remains the sole defining genetic lesion in aGCTs, with other variants being exceedingly rare.

Functional studies in the KGN granulosa cell line confirm retention of nuclear localization and transactivation ability of p.Cys134Trp except for altered co-regulation with SMAD3 on select promoters, suggesting a subtle neomorphic effect rather than simple loss of function ([PMID:20098707]). Proteomic analyses further show that p.Cys134Trp fails to integrate certain protein-protein interactions, including differential binding to GMEB1 and NR2C1, which may contribute to tumorigenesis ([PMID:22544055]).

Overall, the FOXL2 c.402C>G (p.Cys134Trp) somatic mutation represents a definitive diagnostic biomarker for adult-type ovarian granulosa cell tumors. Routine sequencing for this hotspot mutation can aid in accurate diagnosis and may inform targeted research into FOXL2-driven oncogenesis.

Key Take-home: Somatic FOXL2 c.402C>G is a definitive, highly specific molecular marker for diagnosing adult-type granulosa cell tumors.

References

• Modern pathology • 2011 • Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary. PMID:21623383
• Gynecologic oncology • 2011 • FOXL2 C402G mutation detection using MALDI-TOF-MS in DNA extracted from Israeli granulosa cell tumors. PMID:21640373
• Journal of ovarian research • 2014 • Molecular pathogenesis in granulosa cell tumor is not only due to somatic FOXL2 mutation. PMID:25297715
• PloS One • 2010 • Functional exploration of the adult ovarian granulosa cell tumor-associated somatic FOXL2 mutation p.Cys134Trp (c.402C>G). PMID:20098707
• Human molecular genetics • 2012 • Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles. PMID:22544055
• Clinical genetics • 2017 • Genetics and genomics of ovarian sex cord-stromal tumors. PMID:27813081

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