ORIGINAL ARTICLE

A PDGFRA promoter polymorphism, which disrupts the binding of ZNF148, is associated with primitive neuroectodermal tumours and ependymomas

C De Bustos¹, A Smits², B Strömberg³, V P Collins⁴, M Nistér^1,5, G Afink^1,5

¹ Department of Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
² Department of Neuroscience, Neurology, Uppsala University, University Hospital, 751 85 Uppsala, Sweden
³ Department of Women and Child Health, Uppsala University, University Children’s Hospital, 751 85 Uppsala, Sweden
⁴ Department of Pathology, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 QQ, UK
⁵ Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, R8:05 Karolinska Hospital, 17176 Stockholm, Sweden

Correspondence to:
Correspondence to:
Gijs Afink
Department of Oncology-Pathology, Karolinska Institutet, CCK R8:05 KS, 17176 Stockholm, Sweden;gijs.afink{at}cck.ki.se

Background: Platelet derived growth factor receptor (PDGFR) expression is typical for a variety of brain tumours, while in normal adult brain PDGFR expression is limited to a small number of neural progenitor cells. The molecular mechanisms responsible for the PDGFR expression in tumours are not known, but in the absence of amplification, changes in transcriptional regulation might be an important factor in this process.

Methods and results: We have investigated the link between single nucleotide polymorphisms (SNPs) within the PDGFR gene promoter and the occurrence of brain tumours (medulloblastomas, supratentorial primitive neuroectodermal tumours (PNETs), ependymal tumours, astrocytomas, oligodendrogliomas, and mixed gliomas). These SNPs give rise to five different promoter haplotypes named H1 and H2–. It is apparent from the haplotype frequency distribution that both PNET (10-fold) and ependymoma (6.5-fold) patient groups display a significant over-representation of the H2 haplotype. The precise functional role in PDGFR gene transcription for the H2 haplotype is not known yet, but we can show that the H2 haplotype specifically disrupts binding of the transcription factor ZNF148 as compared to the other promoter haplotypes.

Conclusions: The specific over-representation of the H2 haplotype in both patients with PNETs and ependymomas suggests a functional role for the ZNF148/PDGFR pathway in the pathogenesis of these tumours.

Abbreviations: EMSA, electrophoretic mobility shift assay; PDGFR, platelet derived growth factor receptor; PNET, primitive neuroectodermal tumour; SNP, single nucleotide polymorphism

Keywords: brain; cancer; platelet derived growth factor; single nucleotide polymorphism; transcription

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