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

Jamieson, Stacey; Bützow, Ralf; Andersson, Noora; Alexiadis, Maria; Unkila‐Kallio, Leila; Heikinheimo, Markku; Fuller, Peter J.; Anttonen, Mikko

doi:10.1038/modpathol.2010.145

Cited by 200 publications

(194 citation statements)

References 39 publications

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“…Our findings differ from those reported recently by Jamieson et al, 16 who found that levels were similar in all cases and controls studied, irrespective of their adult or juvenile nature. In our series, both tumor types expressed higher levels of FOXL2 mRNA than normal ovaries, especially granulosa cell tumors.…”

Section: Discussioncontrasting

confidence: 99%

“…10 Previous studies have shown that this mutation is specific for the adult type granulosa cell tumors and is present in up to 95-97% of these tumors. 10,16 Recently, mutant FOXL2 has been found to induce lower levels of apoptosis compared with wild-type FOXL2. 17 The purpose of this investigation was to find out whether FOXL2 mutation and expression levels have a role in the pathogenesis of juvenile and adult granulosa cell tumors as well as its potential value as a prognostic factor.…”

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confidence: 99%

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Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

et al. 2011

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Recently, mutation of the FOXL2 gene has been consistently identified in adult granulosa cell tumors of the ovary. The purpose of this study is to investigate whether the FOXL2 mutation and mRNA expression have a role in the pathogenesis of juvenile and adult granulosa cell tumors and influence tumor progression. Thirty-four adult granulosa cell tumors and 20 juvenile granulosa cell tumors were examined for the presence of the FOXL2 (C402G) mutation. Expression levels were studied by quantitative PCR and immunohistochemistry. We found that FOXL2 (C402G) mutation was present in 19/27 (70%) of the adult type tumors but in none of the juvenile granulosa cell tumors (0/18). No correlation was encountered between the presence of FOXL2 mutation and various clinicopathologic parameters except for the presence of a different sex-cord component, which was more frequently found in the subgroup of wild-type adult granulosa cell tumors than in the mutated tumors. Patients with tumors harboring the FOXL2 (C402G) mutation had a worse disease-free survival than those with the wild-type gene. Expression levels of FOXL2 mRNA had an impact on disease-free survival in both adult and juvenile granulosa cell tumors. We also found that the mutated tumors had a higher immunohistochemical expression of the FOXL2 protein, and there was a linear correlation between mRNA and immunohistochemical FOXL2 expression in both adult and juvenile granulosa cell tumors. Patients with juvenile granulosa cell tumors and higher FOXL2 protein expression had worse overall survival and disease-free survival than those with negative or weakly immunoreactive tumors. Our data suggest that FOXL2 mutation and mRNA expression are of prognostic importance in both adult and juvenile granulosa cell tumors.

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Section: Discussioncontrasting

confidence: 99%

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confidence: 99%

Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

et al. 2011

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“…7,29,37,38 The latter were verified to possess the c.402C-G (p.C134W) mutation in FOXL2 5 and the mutation frequency of 95% corresponds to other published GCT series. [2][3][4] All histological diagnoses were carefully reevaluated, 29 patient charts were reviewed to obtain clinical data and recurrences were updated as of September 2009.…”

Section: Materials and Methods Human Tissue Samplesmentioning

confidence: 60%

“…52 Accordingly, several previous studies utilizing human GCT tissue series (reviewed in Fuller and Chu 53 ) have focused on genes and factors involved in the normal granulosa cell function. 5,7,29,54 We now describe the expression patterns of the AMH-signaling pathway components in GCT in detail and show evidence for AMH being a growth inhibitor for GCT. Previously, AMHRII positivity and AMH responsiveness have been reported in ovarian cancers originating from the Müllerian duct derivatives.…”

Section: Discussionmentioning

confidence: 85%

Anti-Müllerian hormone inhibits growth of AMH type II receptor-positive human ovarian granulosa cell tumor cells by activating apoptosis

Anttonen

Färkkilä

Tauriala

et al. 2011

Laboratory Investigation

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Ovarian granulosa cell tumors (GCTs) are sex cord stromal tumors that constitute 3-5% of all ovarian cancers. GCTs usually present with an indolent course but there is a high risk of recurrence, which associates with increased mortality, and targeted treatments would be desirable. Anti-Mü llerian hormone (AMH), a key factor regulating sexual differentiation of the reproductive organs, has been implicated as a growth inhibitor in ovarian cancer. GCTs and normal granulosa cells produce AMH, but its expression in large GCTs is usually downregulated. Further, as the lack of specific AMHsignaling pathway components leads to GCT development in mice, we hypothesized that AMH inhibits growth of GCTs. Utilizing a large panel of human GCT tissue samples, we found that AMH type I receptors (ALK2, ALK3 and ALK6) and type II receptor (AMHRII), as well as their downstream effectors Smad1/5, are expressed and active in GCTs. AMHRII expression was detected in the vast majority (96%) of GCTs and correlated with AMH mRNA and protein expression. AMH mRNA level was low in large GCTs, confirming previous findings on low-AMH protein expression in large human as well as mouse GCTs. To study the functional role of AMH in this peculiar ovarian cancer, we utilized a human GCT cell line (KGN) and 10 primary GCT cell cultures. We found that the AMH-Smad1/5-signaling pathway was active in these cells, and that exogenous AMH further activated Smad1/5 in KGN cells. Furthermore, AMH treatment reduced the number of KGN cells and primary GCT cells, with increasing amounts of AMH leading to augmented activation of caspase-3 and subsequent apoptosis. All in all, these data support the premise that AMH is a growth inhibitor of GCTs.

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“…[1][2][3][5][6][7] To date PubMed indexed reports cite a total of 290 adult-type granulosa cell tumors that have been tested for the FOXL2 mutation of which 267 (92%)…”

Section: Discussionmentioning

confidence: 99%

FOXL2 molecular testing in ovarian neoplasms: diagnostic approach and procedural guidelines

Kommoss

Anglesio

Mackenzie³

et al. 2013

Modern Pathology

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A single, recurrent somatic point mutation (402C-G) in FOXL2 has been described in almost all adult-type granulosa cell tumors but not other ovarian neoplasms. Histopathological features of adult-type granulosa cell tumors can be mimicked by a variety of other tumors, making diagnosis of adult-type granulosa cell tumor challenging. It has been suggested that molecular testing for FOXL2 mutation might be a useful tool in the diagnosis of adult-type granulosa cell tumors. The aim of this study was to demonstrate how testing for the FOXL2 mutation can be used in a gynecological pathology consultation service and to establish clear procedural guidelines for FOXL2 testing. Immunohistochemistry for FOXL2 was done using an anti-FOXL2 polyclonal antiserum. If immunohistochemistry was positive, FOXL2 mutation status was subsequently analyzed using a TaqMan assay. A dilution experiment was done to assess the sensitivity and minimum tumor cellularity requirements for our TaqMan assay. Twenty problematic cases were assessed, where the differential diagnosis after the initial investigations included adult-type granulosa cell tumors. Differential diagnoses included: thecoma, Sertoli-Leydig cell tumor, juvenile granulosa cell tumor, endometrial stromal sarcoma and others. In all cases, FOXL2 immunohistochemistry was positive and in six samples the FOXL2 mutation was detected, thus confirming a diagnosis of adult-type granulosa cell tumor. The TaqMan assay was able to reliably detect the FOXL2 mutation with input DNA in the range of 2.5-20 ng, and with a minimum of 25% tumor cell nuclei. The analysis of the FOXL2 mutational status in clinical samples is a useful diagnostic tool in situations where the differential diagnosis is between adult-type granulosa cell tumor and other ovarian tumors. The TaqMan assay requires a minimum of 2.5 ng DNA, with optimal assay performance for 5 to 10 ng DNA input. Laser capture or needle-macrodissection should be undertaken to enrich samples with tumor cell content below 25%.

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

Cited by 200 publications

References 39 publications

Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary

Anti-Müllerian hormone inhibits growth of AMH type II receptor-positive human ovarian granulosa cell tumor cells by activating apoptosis

FOXL2 molecular testing in ovarian neoplasms: diagnostic approach and procedural guidelines

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