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

Background: Platelet derived growth factor receptor a (PDGFRa) expression is typical for a variety of brain tumours, while in normal adult brain PDGFRa expression is limited to a small number of neural progenitor cells. The molecular mechanisms responsible for the PDGFRa 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 PDGFRa 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 H2a–d. 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 H2d haplotype. The precise functional role in PDGFRa gene transcription for the H2d haplotype is not known yet, but we can show that the H2d haplotype specifically disrupts binding of the transcription factor ZNF148 as compared to the other promoter haplotypes. Conclusions: The specific over-representation of the H2d haplotype in both patients with PNETs and ependymomas suggests a functional role for the ZNF148/PDGFRa pathway in the pathogenesis of these tumours.