FSH-regulated gene expression profiles in ovarian tumours and normal ovaries

Chu, Simon; Rushdi, Sonya; Zumpe, Emma Therese; Mamers, Pamela; Healy, David; Jobling, Tom; Burger, Henry; Fuller, Peter J.

doi:10.1093/molehr/8.5.426

Cited by 75 publications

(85 citation statements)

References 51 publications

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“…4,22 These properties together with the gene expression profiles are characteristic of proliferating preovulatory granulosa cells. [5][6][7] Previous studies of granulosa cell tumors have sought altered expression and/or mutations of genes expressed in normal proliferating granulosa cells, 6 including transcription factors such as GATA4, 7,23 and genes commonly mutated in human malignancy, 4 including ras 16 and PTEN/PI3-kinase.…”

Section: Discussionmentioning

confidence: 99%

“…5,[14][15][16][17][18][19] Normal ovarian tissue was obtained from premenopausal women who had undergone elective hysterectomy with oophorectomy for a range of conditions not associated with ovarian malignancy (Supplementary Table 1). RNA from the tissue and the two granulosa cell tumorderived cell lines was extracted using the guanidine thiocyanate/cesium chloride method as described previously.…”

Section: Melbournementioning

confidence: 99%

“…Indeed, granulosa cell tumors exhibit a gene expression profile consistent with that of normal proliferating granulosa cells of preantral follicles. [5][6][7] A range of these genes, as well as genes commonly mutated in human malignancy, have been examined for mutations and/or altered expression in granulosa cell tumors without success. 4 This situation abruptly changed in 2009 with the report of a somatic mutation in the FOXL2 gene (C402G; Cys134Trp) that was present in 97% of adult granulosa cell tumors.…”

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

et al. 2010

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Granulosa cell tumors of the ovary represent B5% 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 wildtype 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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Section: Discussionmentioning

confidence: 99%

Section: Melbournementioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2010

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“…Indeed, GCTs exhibit a gene expression profile consistent with that of normal proliferating granulosa cells of preantral follicles (6)(7)(8).…”

Section: Introductionmentioning

confidence: 88%

FOXL2 molecular status in adult granulosa cell tumors of the ovary: A study of primary and metastatic cases

Zannoni

Improta²,

Petrillo

et al. 2016

Oncology Letters

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Abstract. Granulosa cell tumors (GCTs) of the ovary are uncommon neoplasms, accounting for ~5% of all malignant ovarian tumors. GCTs are a relatively homogeneous group of tumors, categorized into two distinct subtypes, juvenile GCT and adult GCT (AGCT), likely arising from a limited set of molecular events usually involving the disruption of pathways that regulate granulosa cell proliferation. In the present study, the presence of forkheadbox L2 (FOXL2) c.402C>G mutation was investigated in a series of 42 samples of primary and metastatic AGCT of the ovary. The samples consisted of 37 primary and 5 metastatic ovarian AGCTs from 37 patients. FOXL2 mutational status was evaluated using a pyrosequencing approach on 2.5-µm sections of formalin-fixed paraffin-embedded tissue. FOXL2 c.402C>G mutation was found in 33/37 (89.2%) primary AGCTs and in 4/5 (80.0%) metastases, with the molecular status of the metastases recapitulating that of the primary tumors (4 mutated cases and 1 wild-type case). Overall, FOXL2 mutation is present in the majority of primary and metastatic AGCTs, and could be used as a valid tool in the diagnosis of the disease and in cases of metastatic lesions from an unknown primary origin. Moreover the concordance of FOXL2 molecular status in primary and associated metastases suggests its early appearance and genomic stability in AGCT tumorigenesis.

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“…The PRKAR2B gene encodes one of the regulatory subunits of the PKA complex. The PRKAR2B gene is an early response gene for gonadotropin-treated ovarian cells (Chu et al 2002). The expression of PRKAR2B and RSG3 in preovulatory estrogenic follicles may imply a mechanism through which the preovulatory follicle restrains the cAMP signal and prevents premature luteinization.…”

Section: Genbankmentioning

confidence: 99%

Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression

Ağca

Ries²,

Kolath³

et al. 2006

Reproduction

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The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (nZ11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; nZ6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; nZ5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P!0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function.

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FSH-regulated gene expression profiles in ovarian tumours and normal ovaries

Cited by 75 publications

References 51 publications

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

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

FOXL2 molecular status in adult granulosa cell tumors of the ovary: A study of primary and metastatic cases

Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression

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