Pdgfr‐α in 1p/19q LOH oligodendrogliomas

Hartmann, Christian; Xu, Xiangli; Bartels, Gesine; Holtkamp, Nikola; Gonzales, Isis Atallah; Tallen, Gesche; Deimling, Andreas von

doi:10.1002/ijc.20525

Cited by 10 publications

(4 citation statements)

References 8 publications

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“…Here, we investigated the prevalence of PDGFRA -activating mutations and gene amplification in gliomas. In agreement with previous studies (Hartmann et al , 2004; Rand et al , 2005; Reis et al , 2005; Sihto et al , 2005; Wen et al , 2006; McLendon et al , 2008; Parsons et al , 2008), no PDGFRA -activating mutations were found. However, four silent mutations and an intronic insertion were identified.…”

Section: Discussionsupporting

confidence: 93%

Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas

et al. 2009

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Background:Malignant gliomas are the most prevalent type of primary brain tumours but the therapeutic armamentarium for these tumours is limited. Platelet-derived growth factor (PDGF) signalling has been shown to be a key regulator of glioma development. Clinical trials evaluating the efficacy of anti-PDGFRA therapies on gliomas are ongoing. In this study, we intended to analyse the expression of PDGFA and its receptor PDGFRA, as well as the underlying genetic (mutations and amplification) mechanisms driving their expression in a large series of human gliomas.Methods:PDGFA and PDGFRA expression was evaluated by immunohistochemistry in a series of 160 gliomas of distinct World Health Organization (WHO) malignancy grade. PDGFRA-activating gene mutations (exons 12, 18 and 23) were assessed in a subset of 86 cases by PCR—single-strand conformational polymorphism (PCR-SSCP), followed by direct sequencing. PDGFRA gene amplification analysis was performed in 57 cases by quantitative real-time PCR (QPCR) and further validated in a subset of cases by chromogenic in situ hybridisation (CISH) and microarray-based comparative genomic hybridisation (aCGH).Results:PDGFA and PDGFRA expression was found in 81.2% (130 out of 160) and 29.6% (48 out of 160) of gliomas, respectively. Its expression was significantly correlated with histological type of the tumours; however, no significant association between the expression of the ligand and its receptor was observed. The absence of PDGFA expression was significantly associated with the age of patients and with poor prognosis. Although PDGFRA gene-activating mutations were not found, PDGFRA gene amplification was observed in 21.1% (12 out of 57) of gliomas. No association was found between the presence of PDGFRA gene amplification and expression, excepting for grade II diffuse astrocytomas.Conclusion:The concurrent expression of PDGFA and PDGFRA in different subtypes of gliomas, reinforce the recognised significance of this signalling pathway in gliomas. PDGFRA gene amplification rather than gene mutation may be the underlying genetic mechanism driving PDGFRA overexpression in a portion of gliomas. Taken together, our results could provide in the future a molecular basis for PDGFRA-targeted therapies in gliomas.

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Section: Discussionsupporting

confidence: 93%

Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas

et al. 2009

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“…The second variation caused a change in codon 478 from serine to proline which has been reported for malignant peripheral nerve sheath tumors and gliomas. 26,28 These variations were not observed in normal tonsil tissues. All cases analyzed showed a silent mutation in exon 12 of PDGFRA.…”

Section: Polymorphisms Observed In Receptor Tyrosine Kinasesmentioning

confidence: 78%

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Kartha

Sundram

2008

Modern Pathology

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Merkel cell carcinoma is a rare and aggressive form of skin cancer of neuroendocrine origin. Its treatment involves wide excision and radiotherapy but no effective therapy exists for advanced disease. Upregulation of the platelet-derived growth factor receptor family of tyrosine kinases, PDGFRA and KIT, has a crucial role in cancer development. Several studies have shown expression of the tyrosine kinase receptor KIT (CD117) in Merkel cell carcinoma. In this study, we examined the expression and mutational status of KIT and PDGFRA in 14 primary and 18 metastatic Merkel cell carcinoma. The expression of KIT and PDGFRA and their respective ligands, stem cell factor (SCF) and PDGFA, was assessed by immunohistochemistry. In addition, we analyzed KIT exons 9, 11, 13 and 17, and PDGFRA exons 10, 12 and 18 for the presence of activating mutations. We found that only 53% of cases of Merkel cell carcinoma expressed KIT, which was mostly seen as diffuse weak staining, and SCF expression was observed only in 31% of cases. In contrast, 87 and 81% of cases expressed PDGFRA and PDGFA, respectively. We observed coexpression of SCF and KIT in only 5 of 32 cases (16%) whereas 25 of 31 cases (81%) showed coexpression of PDGFRA and its ligand PDGFA. While we documented silent mutations in exon 17 of KIT and exons 10, 12 and 18 of PDGFRA, we were not able to identify any known activating mutations. Our results indicate that there is no correlation between positive immunostaining and occurrence of activating mutations in KIT and PDGFRA. Moreover, the presence of KIT/SCF and PDGFRA/PDGFA coexpression in a proportion of cases may indicate an autocrine/paracrine stimulation loop. We think therefore that imatinib mesylate is less likely to be an effective therapy for Merkel cell carcinoma, unless activating mutations exist in other exons of these receptor kinases.

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“…However, functional analysis of PDGFRA harboring the exon 10 S478P substitution demonstrated ligand dependence, suggesting that the base change is not a gain‐of‐function mutation . The S478P substitution has only rarely been reported in gastrointestinal tumors, malignant peripheral nerve sheath tumors and gliomas . Furthermore, this base change is present in 13.4–25% of healthy individuals suggesting that it may represent a single nucleotide polymorphism instead of a true mutation …”

Section: Discussionmentioning

confidence: 99%

Specific analysis of KIT and PDGFR‐alpha expression and mutational status in Merkel cell carcinoma

2013

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Pdgfr‐α in 1p/19q LOH oligodendrogliomas

Cited by 10 publications

References 8 publications

Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas

Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Specific analysis of KIT and PDGFR‐alpha expression and mutational status in Merkel cell carcinoma

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