Methylation of PTCH1, the Patched-1 gene, in a panel of primary medulloblastomas.
The Sonic hedgehog (Shh) pathway is aberrantly activated in a subset of the most common malignant pediatric brain tumor, medulloblastoma (MB). Shh pathway activity is measured by expression of the target genes in the GLI family, MYCN and PTCH1, a tumor suppressor and negative regulator of the pathway. Promoter methylation of tumor suppressors is implicated in tumor formation by gene silencing. In this study, we examined whether the proximal promoter of the PTCH1 gene (variant exon 1B) is methylated in some cases of MB. The cases in which we anticipated the highest likelihood of methylation were chosen based on gene expression of indicators of Shh pathway activity. Of 21 primary MBs, four exhibited robust mRNA expression of GLI1 and MYCN as well as low or absent PTCH1 expression, suggesting Shh pathway activity in the absence of PTCH1. The methylation profile of these cases was determined by the bisulfite sequencing method and compared to the profiles of five unaffected pediatric cerebellum controls. Contrary to our hypothesis, there was no evidence of methylation in the PTCH1-1B promoter in the MB cases examined, nor was there methylation in the control cerebellum samples. Future directions include examination of distal regions of the PTCHlb promoter as well as alternative exon variants, most notably the CpG island containing PTCH1-1C promoter.
Pritchard
Joel I
JI
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Olson
James M
JM
D001578:Benzopyrans / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000235:genetics*; D002531:Cerebellum / Q000378:metabolism; D002648:Child; D019175:DNA Methylation; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics*; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
C499785:7-(3-(2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy)propoxy)-3,4-dihydro-2-methyl-2H-benzopyran-2-carboxylic acid; D001578:Benzopyrans; C400551:GLI1 protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1