Haplotype-specific expression of the human PDGFRA gene correlates with the risk of glioblastomas.
Aberrant expression of the platelet-derived growth factor alpha-receptor (PDGFRA) gene has been associated with various diseases, including neural tube defects and gliomas. We have previously identified 5 distinct haplotypes for the PDGFRA promoter region, designated H1, H2alpha, H2beta, H2gamma and H2delta. Of these haplotypes H1 and H2alpha are the most common, whereby H1 drives low and H2alpha high transcriptional activity in transient transfection assays. Here we have investigated the role of these PDGFRA promoter haplotypes in gliomagenesis at both the genetic and cellular level. In a case-control study on 71 glioblastoma patients, we observed a clear underrepresentation of H1 alleles, with pH1 = 0.141 in patients and pH1 = 0.211 in a combined Western European control group (n = 998, p < 0.05). Furthermore, in 3 out of 4 available H1/H2alpha heterozygous human glioblastoma cell lines, H1-derived mRNA levels were more than 10-fold lower than from H2alpha, resulting at least in part from haplotype-specific epigenetic differences such as DNA methylation and histone acetylation. Together, these results indicate that PDGFRA promoter haplotypes may predispose to gliomas. We propose a model in which PDGFRA is upregulated in a haplotype-specific manner during neural stem cell differentiation, which affects the pool size of cells that can later undergo gliomagenesis.
Toepoel
Mascha
M
Department of Cell Biology FNWI, Radboud University Nijmegen, Nijmegen, The Netherlands.
Joosten
Paul H L J
PHLJ
Department of Cell Biology FNWI, Radboud University Nijmegen, Nijmegen, The Netherlands.
Knobbe
Christiane B
CB
Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany.
Afink
Gijs B
GB
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Zotz
Rainer B
RB
Department of Hemostasis and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
Steegers-Theunissen
Regine P M
RPM
Erasmus University Medical Center, Rotterdam, The Netherlands.
Reifenberger
Guido
G
Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany.
van Zoelen
Everardus J J
EJJ
Department of Cell Biology FNWI, Radboud University Nijmegen, Nijmegen, The Netherlands.
D000107:Acetylation; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D019175:DNA Methylation; D004591:Electrophoresis, Polyacrylamide Gel; D005060:Europe / Q000453:epidemiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005909:Glioblastoma / Q000737:chemistry* / Q000453:epidemiology / Q000235:genetics; D006239:Haplotypes; D006657:Histones / Q000378:metabolism; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012307:Risk Factors; D015854:Up-Regulation
D006657:Histones; D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha