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


CONCLUSIONS
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.
Martinho
O
O
Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, 4710 Braga, Portugal.
Longatto-Filho
A
A
Lambros
M B K
MB
Martins
A
A
Pinheiro
C
C
Silva
A
A
Pardal
F
F
Amorim
J
J
Mackay
A
A
Milanezi
F
F
Tamber
N
N
Fenwick
K
K
Ashworth
A
A
Reis-Filho
J S
JS
Lopes
J M
JM
Reis
R M
RM
D000293:Adolescent; D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000737:chemistry* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D005910:Glioma / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010982:Platelet-Derived Growth Factor / Q000032:analysis* / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction
D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha
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