No evidence for V600E <i>BRAF</i> mutation in the seminoma cell line TCam‐2

Goddard, N. C.; McIntyre, Alan; Gilbert, Duncan C.; Kitazawa, Sohei; Shipley, Janet

doi:10.1002/gcc.20799

Cited by 6 publications

(3 citation statements)

References 21 publications

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“…Interestingly, the TCAM2 seminoma cell line was initially reported to exhibit a BRAF mutation (de Jong et al, 2008). However, other studies did not corroborate these findings even in other germ cell tumor cell lines (Goddard et al, 2010;Feldman et al, 2014).…”

Section: Discussioncontrasting

confidence: 42%

Absence of microsatellite instability andBRAF(V600E) mutation in testicular germ cell tumors

et al. 2016

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SUMMARYTesticular germ cell tumors (TGCT) are the most common malignant neoplasm in young men. DNA mismatch repair deficiency can lead to microsatellite instability (MSI), an important mechanism of genetic instability. A mutation of the BRAF gene has been implicated in the pathogenesis of several solid tumors and has recently become an important therapeutic target. The role of MSI and BRAF gene mutation in TGCT, particularly in refractory disease, is poorly understood and reported findings are controversial. In this study, we aimed to determine the frequency and clinical impact of MSI status and BRAF mutations in TGCT. DNA was isolated from formalin-fixed paraffin embedded (FFPE) tissue from 150 TGCT cases. The MSI phenotype was evaluated using multiplex PCR for five quasimonomorphic mononucleotide repeat markers. Exon 15 of the BRAF oncogene (V600E) was analyzed by PCR, followed by direct sequencing. Sixteen percent of cases were considered to have refractory disease. In a small subset of cases (17 for MSI and 18 for BRAF), the quantity and quality of DNA recovery were poor and therefore, were unable to be analyzed. The remaining 133 TGCT cases showed a complete absence of MSI. Of the 132 cases successfully evaluated for BRAF mutations, all were V600E wild-type. In conclusion, despite a distinct response of testicular germ cell tumors to therapy, microsatellite instability, and the BRAF V600E mutation were absent in all testicular germ cell tumors tested in this study.

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Section: Discussioncontrasting

confidence: 42%

Absence of microsatellite instability andBRAF(V600E) mutation in testicular germ cell tumors

et al. 2016

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“…These cells express OCT3 ⁄ 4 and NANOG, as well as SOX17, but not SOX2 or CD30, a profile common to seminomas; TCam-2 cells also express both KIT and KITLG (de Jong et al, 2008;Stoop et al, 2008). Although TCam-2 cells harbour few proto-oncogene mutations, a mutation has been identified at the BRAF locus (V600E), suggesting the potential for dysregulated MAP kinase ⁄ ERK signalling; however, a subsequent report indicates that this mutation may not be a consistent feature of the cell line (Goddard et al, 2010), raising the need to establish parameters by which TCam-2 cell function can be assessed in the context of its seminoma origin.…”

Section: Introductionmentioning

confidence: 99%

TCam‐2 seminoma cell line exhibits characteristic foetal germ cell responses to TGF‐beta ligands and retinoic acid

et al. 2011

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Germ cell testicular cancer is understood to arise during embryogenesis, based on the persistence of embryonic germ cell markers in carcinoma in situ and seminoma. In this study, we examine the potential of the seminoma-derived TCam-2 cell line to be used as representative in functional analyses of seminoma. We demonstrate expression of several early germ cell markers, including BLIMP1, OCT3/4, AP2γ, NANOG and KIT. Many TGF-beta superfamily receptors and downstream transcription factors are also present in these cells including the normally foetal ACTRIIA receptor, indicating potential responsiveness to TGF-beta superfamily ligands. Treatment with BMP4 or RA induces a significant increase in ACTRIA, ACTRIIA and ACTRIIB transcripts, whereas activin A decreases ACTRIB. BMP4 and RA each support TCam-2 survival and/or proliferation. In addition, despite increased KIT mRNA levels induced by BMP4, RA and activin A, activin A does not improve survival or proliferation. The capacity for BMP4 and retinoic acid to enhance foetal germ cell survival and proliferation/self-renewal has been demonstrated in mice, but not previously tested in humans. This study is the first to demonstrate a functional response in seminoma cells, using a well-characterized cell line, consistent with their foetal germ cell-like identity.

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“…BRAF mutations that regulate the MAP kinase/ERK pathway and play an important role in regulating cell proliferation and differentiation are also reported in GCT, although they appear to be conspicuously absent in seminoma (McIntyre et al ., ; Goddard et al ., ; Pedersen et al ., ). BRAF mutations, which are correlated with microsatellite instability (MSI), have been associated with platinum resistance (Honecker et al ., ).…”

Section: Mutations and Signaling Pathways Involved In Germ Cell Tumorsmentioning

confidence: 99%

New insights into germ cell tumor genomics

et al. 2019

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Background: Testicular germ cell tumors (GCTs) represent the most common malignancy in young men. While GCTs represent a model for curable solid tumors due to exquisite chemosensitivity, mortality for patients with GCT comprises the most life years lost for non-pediatric malignancies. Given limited options for patients with platinum-resistant disease, improved insight into GCT biology could identify novel therapeutic options for patients with platinum-resistant disease. Recent studies into molecular characteristics of both early stage and advanced germ cell tumors suggest a role for rationally targeted agents and potentially immunotherapy. Recent developments: Recent GWAS meta-analyses have uncovered additional susceptibility loci for GCT and provide further evidence that GCT risk is polygenic. Chromosome arm level amplifications and reciprocal loss of heterozygosity have been described as significantly enriched in GCT compared to other cancer types. Contemporary analyses confirm ubiquitous gain of isochromosome 12 and mutations in addition to previously described GCT-associated genes such as KIT and KRAS. Alterations within the TP53-MDM2 signal transduction pathway appear to be enriched among patients with platinum-resistant disease. Potentially actionable targets, including alterations in TP53-MDM2, Wnt/b-catenin, PI3K, and MAPK signaling, are present in significant proportions of patients with platinum-resistant disease and may be exploited as therapeutic options. Pre-clinical and early clinical data also suggest a potential role for immunotherapy among patients with GCTs. Conclusion: Molecular characterization of GCT patients may provide biologic rationale for novel treatment options in patients with platinum-resistant disease.

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No evidence for V600E BRAF mutation in the seminoma cell line TCam‐2

Cited by 6 publications

References 21 publications

Absence of microsatellite instability andBRAF(V600E) mutation in testicular germ cell tumors

Absence of microsatellite instability andBRAF(V600E) mutation in testicular germ cell tumors

TCam‐2 seminoma cell line exhibits characteristic foetal germ cell responses to TGF‐beta ligands and retinoic acid

New insights into germ cell tumor genomics

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