Adult-type granulosa cell tumors are molecularly characterized by a pathognomonic somatic missense point mutation 402C->G (C134W) in the transcription factor FOXL2.
Recently, we reported the identification of a somatic FOXL2 402C-->G mutation that is present in virtually all adult-type granulosa cell tumors, but not in a wide range of other tumor types.
FOXL2 mutation analysis is a useful adjunct in distinguishing between diffuse adult granulosa cell tumor (mutation present) and cellular fibroma (mutation absent).
Overexpression of wild-type but not C134W mutant FOXL2 enhances GnRH-induced cell apoptosis by increasing GnRH receptor expression in human granulosa cell tumors.
Our study shows that half of granulosa theca cell tumors harbor the same FOXL2 mutation that characterizes adult granulosa cell tumors but there is no outcome evidence to guide whether mutation status should alter the classification of the tumor or the management of the patient.
To assess whether FOXL2p.C134W mutation may play a role in the development of human ovarian tumors in the Japanese, we investigated the FOXL2 codon 134 mutation and protein expression of inhibin-α, bone morphogenetic protein 2 (BMP2) and follistatin (FST) in Japanese patients with granulosa cell tumor (GCT) of the ovary and other ovarian tumors.
Recently, a single point missense mutation (C134W) was found in the FOXL2 gene in approximately 95% of adult-type granulosa cell tumors, suggesting a key role for FOXL2 in these tumors.
FOXL2 ctDNA mutations were detected in the plasma of 12 of 33 AGCT patients (36%), with both primary (6 of 17, 35%) and recurrent (6 of 31, 19%) tumors.
In addition to proving that the KGN cell line is a useful model to study A-GCTs, these data show that the c.402C>G mutation in FOXL2 is not commonly found in a wide variety of other cancers and therefore it is likely pathognomonic for A-GCTs and closely related tumors.
The results of this case study indicated that although FOXL2 402C > G mutation determines the development of granulosa cell tumor, PMS2 mutation may be the initial driver of carcinogenesis.
We undertook this study to verify the presence of the FOXL2Cys134Trp mutation in two geographically independent cohorts of granulosa cell tumors and to examine the expression pattern of FOXL2 in these tumors.
Mutational analysis (c.402C>G) of the FOXL2 gene and immunohistochemical expression of the FOXL2 protein in testicular adult type granulosa cell tumors and incompletely differentiated sex cord stromal tumors.
FOXL2 mutation was present in 44 out of 47 adult granulosa cell tumors (94%), in 3 out of 8 Thecomas (37%), in 1 out of 10 Sertoli-Leydig cell tumors (SLSTs) (10%) and in 3 out of 5 undifferentiated-SCSTs (Und-SCSTs) (60%).