The FOXL2 C134W mutation is characteristic of adult granulosa cell tumors of the ovary

Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia.
Modern Pathology (Impact Factor: 6.19). 11/2010; 23(11):1477-85. DOI: 10.1038/modpathol.2010.145
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Granulosa cell tumors of the ovary represent ∼5% of malignant ovarian cancers. It has recently been reported that 95-97% of adult granulosa cell tumors carry a unique somatic mutation in the FOXL2 gene. We undertook this study to verify the presence of the FOXL2 Cys134Trp mutation in two geographically independent cohorts of granulosa cell tumors and to examine the expression pattern of FOXL2 in these tumors. A total of 56 tumors with the histological diagnosis of adult granulosa cell tumor from two centers, Melbourne and Helsinki, were examined for the presence of the mutation using direct sequence analysis. Two granulosa cell tumor-derived cell lines, COV434 and KGN, three juvenile granulosa cell tumors and control tissues were also examined. The expression of the FOXL2 gene was determined using quantitative RT-PCR and/or immunohistochemistry. We found that 52 of the 56 adult granulosa cell tumors harbor the mutation, of which three were hemi/homozygous. Of the four cases with wild-type FOXL2 sequence, reappraisal suggests that three may have been misclassified at primary diagnosis. The KGN cells were heterozygous for the mutation, whereas the COV434 cells had a wild-type FOXL2 genotype. The expression levels of FOXL2 were similar across the adult granulosa cell tumors and the normal ovary controls; one mutation-negative granulosa cell tumor had high FOXL2 mRNA levels, whereas the COV434 cells and two of the three juvenile granulosa cell tumors lacked the expression of FOXL2. Our data provide confirmation of the frequent presence of the FOXL2 C134W mutation in adult granulosa cell tumors and demonstrate that the mutation is not associated with altered FOXL2 expression. The mutation analysis may be a useful tool to differentiate particularly between cell-rich diffuse granulosa cell tumors and mitotically active sex cord-stromal tumors. This unique FOXL2 mutation appears to be characteristic of adult granulosa cell tumors.

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Available from: Ralf Butzow, Apr 04, 2014
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    • "Moreover, FOXL2 is expressed in all types of ovarian sex cord–stromal tumors, except for steroid cell tumors [8]. A FOXL2 missense point mutation is present in more than 90% of adult granulosa cell tumors [9]. Nonovarian tumors such as PMC, HBC, and MEST share the distinctive feature of having ovarian-type stroma. "
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    ABSTRACT: FOXL2, a gene encoding a member of the fork-head-winged-helix family of transcription factors, is one of the earliest expressed genes during female gonadal development. It is expressed in normal ovarian stroma and ovarian neoplasms with granulosa cell lineage. Non-ovarian tumors such as pancreatic mucinous cystic neoplasms (PMC), hepatobiliary cystadenomas (HBC), and mixed epithelial and stromal tumor of kidney (MEST), have ovarian-type stroma. Immunohistochemical (IHC) staining with FOXL2, estrogen receptor (ER), and progesterone receptor (PR) were performed on 21 PMC, 13 HBC, and 10 MEST and assessed for nuclear IHC positivity in the tumor stroma. All cases of PMC and HBC demonstrated nuclear reactivity for FOXL2 in the subepithelial stromal cells. 90% of MEST demonstrated nuclear FOXL2 positivity. ER nuclear positivity was demonstrated in 57% PMC, 77% HBC, and 80% of MEST. PR nuclear positivity was present in 67% PMC, 100% HBC and 90% of MEST. Clinical information was available for 37 patients. 78% of the patients had a history of either obesity, heavy alcohol use, or hormone-related therapy. The 2 male patients had histories significant for morbid obesity and chronic alcoholism. FOXL2 is expressed from the early stages of ovarian development and has been shown to be mandatory for normal ovarian function. We have shown that it is also expressed in the aberrant ovarian-type stroma characteristic of PMC, HBC, and MEST. The majority of such patients, including the rare male patients, have risk factors for hormonal abnormalities, such as obesity and hormonal replacement therapy.
    Human pathology 05/2014; 45(5). DOI:10.1016/j.humpath.2013.12.015 · 2.77 Impact Factor
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    • "e l s e v i e r . c o m / l oc a t e / s t e r o i d s finding that has subsequently been confirmed by two independent groups [13] [14]. Although the mutation would appear to be aetiologic or pathognomic, the mechanisms of action of FOXL2 remain to be elucidated. "
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    ABSTRACT: Granulosa cell tumours of the ovary (GCT) express aromatase and produce oestrogens. The ovarian-specific aromatase promoter (pII) is regulated by members of the group 5A nuclear receptor family, SF-1 and LRH-1. Since both SF-1 and LRH-1 are implicated in proliferation and cancer, we hypothesised that alteration in the expression of either or both receptors may be associated with GCT. We therefore determined the expression of LRH-1, SF-1 and aromatase in a cohort of GCT, mucinous and serous cystadenocarcinomas, and normal ovaries. LRH-1 mRNA was present at low level in normal ovary and serous cystadenocarcinoma, but was elevated approximately 30-fold in GCT, and 8-fold in mucinous cystadenocarcinoma, compared to normal ovary. LRH-1 protein expression was confirmed in GCT by immunohistochemistry. SF-1 mRNA was significantly lower that of LRH-1 in all samples and not significantly altered in GCT, compared to normal ovary. Aromatase mRNA was present at low level in normal ovary and serous and mucinous cystadenocarcinoma, and significantly elevated (18-fold) in GCT compared to normal ovary. Despite the coordinate over-expression of both LRH-1 and aromatase in GCT versus normal ovary, their levels did not correlate in individual patients; rather, aromatase expression correlated with that of SF-1. Finally, although both LRH-1 and SF-1 activated aromatase promoter activity in transient transfection studies, gel-shift and chromatin immunoprecipitation data indicated that SF-1, but not LRH-1, bound to the aromatase promoter. We conclude that SF-1 regulates aromatase expression in GCT; over-expression of LRH-1 suggests that this receptor may be involved in the pathogenesis of GCT by mechanisms other than the regulation of aromatase. Its role in this disease therefore warrants further investigation.
    Steroids 03/2013; 78(7). DOI:10.1016/j.steroids.2013.03.001 · 2.64 Impact Factor
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    • "Ovarian tumour tissues [granulosa cell tumors (n=19), mucinous cystadenocarcinomas (n=6) and serous cystadenocarcinomas (n=8)] were obtained from banked tissue samples which had previously been used in different studies 34-36. Normal ovarian tissues were obtained from nine premenopausal women who had undergone elective hysterectomy with oophorectomy for a range of conditions not associated with ovarian malignancy. "
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    ABSTRACT: Objective. The high temperature requirement factor A3 (HtrA3) is a serine protease homologous to bacterial HtrA. Four human HtrAs have been identified. HtrA1 and HtrA3 share a high degree of domain organization and are downregulated in a number of cancers, suggesting a widespread loss of these proteases in cancer. This study examined how extensively the HtrA (HtrA1-3) proteins are downregulated in commonly used cancer cell lines and primary ovarian tumors. Methods. RT-PCR was applied to various cancer cell lines (n=17) derived from the ovary, endometrium, testes, breast, prostate, and colon, and different subtypes of primary ovarian tumors [granulosa cell tumors (n=19), mucinous cystadenocarcinomas (n=6), serous cystadenocarcinomas (n=8)] and normal ovary (n = 9). HtrA3 protein was localized by immunohistochemistry. Results. HtrA3 was extensively downregulated in the cancer cell lines examined including the granulosa cell tumor-derived cell lines. In primary ovarian tumors, the HtrA3 was significantly lower in serous cystadenocarcinoma and granulosa cell tumors. In contrast, HtrA1 and HtrA2 were expressed in all samples with no significant differences between the control and tumors. In normal postmenopausal ovary, HtrA3 protein was localized to lutenizing stromal cells and corpus albicans. In serous cystadenocarcinoma, HtrA3 protein was absent in the papillae but detected in the mesenchymal cyst wall. Conclusion. HtrA3 is more extensively downregulated than HtrA1-2 in cancer cell lines. HtrA3, but not HtrA1 or HtrA2, was decreased in primary ovarian serous cystadenocarcinoma and granulosa cell tumors. This study provides evidence that HtrA3 may be the most relevant HtrA associated with ovarian malignancy.
    Journal of Cancer 02/2013; 4(2):152-64. DOI:10.7150/jca.5702 · 3.27 Impact Factor
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