FOXL2 mutation and large-scale genomic imbalances in adult granulosa cell tumors of the ovary.

Adult granulosa cell tumors (AGCTs) are a rare class of ovarian tumors with recurrent cytogenetic abnormalities including trisomy 12, trisomy 14, monosomy 16/deletion 16q, and monosomy 22. Over 90% contain a missense point mutation (C134W) in the FOXL2 gene at 3q22.3. The relationship between FOXL2 mutation and cytogenetic abnormalities is unclear, although both are presumably early events in tumorigenesis. In addition, FOXL2 C134W mutant allele imbalance has been noted in a minority of AGCTs, but the mechanism for allelic imbalance has not yet been described. We used a microarray platform designed for formalin-fixed, paraffin-embedded (FFPE) tissue specimens, the Affymetrix OncoScan FFPE Express 330K Molecular Inversion Probe (MIP) array, to explore the correlation between genomic imbalances detected by microarray and FOXL2 mutation status detected by pyrosequencing in a series of 21 archived AGCTs. Tumors were characterized by histopathologic features, stage, and alpha-inhibin expression by immunohistochemistry. All tumors were positive for inhibin, and 18/21 tumors contained a FOXL2 mutation. The most common genomic imbalances were a gain of 14q, a loss of 16q, and a loss of 22q. Three tumors showed evidence of FOXL2 mutant allele imbalance by pyrosequencing; microarray revealed a 32.5 Mb deletion encompassing FOXL2 in 1 case and a 70.9 Mb stretch of homozygosity encompassing FOXL2 in the other case. The third case, with a FOXL2 mutant allele imbalance, showed a diminished mutant allele population (32%) despite high estimated tumor content (>90%), suggesting tumor heterogeneity for the mutation. This study provides the first correlation of FOXL2 mutation status and genomic imbalances in AGCTs, and it further elucidates the mechanisms for mutant allele imbalance in cancer.

Geiersbach KB ，Jarboe EA ，Jahromi MS ，Baker CL ，Paxton CN ，Tripp SR ，Schiffman JD ... -  《Cancer Genetics》

FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary.

Al-Agha OM ，Huwait HF ，Chow C ，Yang W ，Senz J ，Kalloger SE ，Huntsman DG ，Young RH ，Gilks CB ... -  《-》

Mutation of FOXL2 in granulosa-cell tumors of the ovary.

Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The pathogenesis of these tumors is unknown. Moreover, their histopathological diagnosis can be challenging, and there is no curative treatment beyond surgery. We analyzed four adult-type GCTs using whole-transcriptome paired-end RNA sequencing. We identified putative GCT-specific mutations that were present in at least three of these samples but were absent from the transcriptomes of 11 epithelial ovarian tumors, published human genomes, and databases of single-nucleotide polymorphisms. We confirmed these variants by direct sequencing of complementary DNA and genomic DNA. We then analyzed additional tumors and matched normal genomic DNA, using a combination of direct sequencing, analyses of restriction-fragment-length polymorphisms, and TaqMan assays. All four index GCTs had a missense point mutation, 402C-->G (C134W), in FOXL2, a gene encoding a transcription factor known to be critical for granulosa-cell development. The FOXL2 mutation was present in 86 of 89 additional adult-type GCTs (97%), in 3 of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%). The mutation was absent in 49 SCSTs of other types and in 329 unrelated ovarian or breast tumors. Whole-transcriptome sequencing of four GCTs identified a single, recurrent somatic mutation (402C-->G) in FOXL2 that was present in almost all morphologically identified adult-type GCTs. Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs.

Shah SP ，Köbel M ，Senz J ，Morin RD ，Clarke BA ，Wiegand KC ，Leung G ，Zayed A ，Mehl E ，Kalloger SE ，Sun M ，Giuliany R ，Yorida E ，Jones S ，Varhol R ，Swenerton KD ，Miller D ，Clement PB ，Crane C ，Madore J ，Provencher D ，Leung P ，DeFazio A ，Khattra J ，Turashvili G ，Zhao Y ，Zeng T ，Glover JN ，Vanderhyden B ，Zhao C ，Parkinson CA ，Jimenez-Linan M ，Bowtell DD ，Mes-Masson AM ，Brenton JD ，Aparicio SA ，Boyd N ，Hirst M ，Gilks CB ，Marra M ，Huntsman DG ... -  《-》

Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W).

Kim JH ，Yoon S ，Park M ，Park HO ，Ko JJ ，Lee K ，Bae J ... -  《-》

FOXL2 mutations in granulosa cell tumors occurring in males.

Lima JF ，Jin L ，de Araujo AR ，Erikson-Johnson MR ，Oliveira AM ，Sebo TJ ，Keeney GL ，Medeiros F ... -  《-》