The Specificity of the FOXL2 c.402C&gt;G Somatic Mutation: A Survey of Solid Tumors

Schrader, Kasmintan A.; Gorbatcheva, Bella; Senz, Janine; Heravi-Moussavi, Alireza; Melnyk, Nataliya; Salamanca, Clara; Maines-Bandiera, Sarah; Cooke, Susanna L.; Leung, Peter C.K.; Brenton, James D.; Gilks, C Blake; Monahan, John E.; Huntsman, David G.

doi:10.1371/journal.pone.0007988

Cited by 84 publications

(72 citation statements)

References 17 publications

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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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“…[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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“…As the FOXL2 mutation is extremely well conserved in most cases of adult-type GCTs and is also GCT-specific over other types of ovarian tumors (Schrader et al, 2009;Shah et al, 2009;Kim et al, 2010), WT FOXL2 may function as a tumor suppressor in normal granulosa cells by efficiently modulating both extrinsic and intrinsic apoptosis signaling pathways. In addition, the disparate apoptotic activities of the two proteins may at least partially account for the pathophysiology of GCT development that occurs by somatic mutation (C134W) of FOXL2.…”

Section: Discussionmentioning

confidence: 99%

“…A recent whole-transcriptome paired-end RNA sequencing study identified a recurrent missense point mutation, 402C-G (C134W), in the FH domain of FOXL2 from ovarian GCTs, and 97% of adult-type GCTs tested were found to possess the mutation (Shah et al, 2009). This somatic FOXL2 mutation has not been observed in other types of tumors, indicating a specific role for FOXL2 in the tumorigenesis of adult-type GCTs (Schrader et al, 2009). However, because it was only recently determined that this mutation is highly prevalent in GTC patients, there is currently no information available regarding how the C134W amino acid substitution in FOXL2 is associated with GTC formation.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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Some mutations in FOXL2 result in premature ovarian failure accompanied by blepharophimosis, ptosis, epicanthus inversus syndrome type I disease, and FOXL2-null mice exhibit developmental defects in granulosa cells. Recently, FOXL2 c.402C4G, a new somatic mutation that leads to a p.C134W change, was found in the majority of adult-type ovarian granulosa cell tumors (GCTs). In this study, we investigated the possible mechanisms by which the C134W mutation contributes to the development of GCTs. Wild-type (WT) and mutant FOXL2 displayed differential apoptotic activities. Specifically, WT FOXL2 induced significant granulosa cell death, but the mutant exhibited minimal cell death. The FOXL2-induced apoptotic response was greatly dependent on caspase 8, BID and BAK because the depletion of any of these three proteins inhibited FOXL2 from eliciting the full apoptotic response. Activation of caspase 8 and subsequent increased production of truncated BID, and oligomerization of BAK, and release of cytochrome c were all associated with the apoptosis induced by WT FOXL2 expression. In contrast, the mutant FOXL2 was unable to elicit the full array of apoptotic signaling responses. In addition, we found differential TNF-R1 (tumor necrosis factor-receptor 1) and Fas (CD95/APO-1) upregulation between the WT and the mutant, and the silencing of TNF-R1 or Fas and the blockage of the death signaling mediated by TNF-R1 or Fas using TNF-Fc or Fas-Fc, respectively, resulted in significant attenuations of FOXL2-induced apoptosis. Moreover, granulosa cells that expressed either WT FOXL2 or mutant exhibited distinct cell death sensitivities on activation of death receptors and deprivation of serum. Thus, the differential activities of FOXL2 and its mutant may partially account for the pathophysiology of GCT development.

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“…8 The mutation was found in only one juvenile granulosa cell tumor 8 and not found in a wide range of other tumors, both gonadal and non-gonadal. 9,10 Curiously, diminished and/or loss of FOXL2 expression has been reported in advanced stage/aggressive juvenile granulosa cell tumors. 11 In this study, we sought to confirm the presence of this mutation in two geographically independent cohorts of granulosa cell tumors and to examine the expression pattern of the FOXL2 gene in these tumors.…”

mentioning

confidence: 99%

“…8,24 The one FOXL2 mutation-negative tumor that remains classified as an adult granulosa cell tumor after reevaluation exhibited true FOXL2 nuclear positivity and high serum inhibin levels. The high frequency with which the mutation occurs in adult granulosa cell tumors and its virtual absence from juvenile granulosa cell tumors and other sex cord-stromal tumor types 8,9,24 argues that this FOXL2 mutation is the key characteristic of an adult-type granulosa cell tumor. Although a minority of thecomas have been reported to be FOXL2 mutation positive, 8,24 these have had granulosa cell-like elements, suggesting that the distinction between these two entities should be based on both genetics and morphology.…”

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confidence: 99%

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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The Specificity of the FOXL2 c.402C>G Somatic Mutation: A Survey of Solid Tumors

Cited by 84 publications

References 17 publications

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

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

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

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

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