title: DNA methylation of developmental genes in pediatric medulloblastomas identified by denaturation analysis of methylation differences.
abstract: DNA methylation might have a significant role in preventing normal differentiation in pediatric cancers. We used a genomewide method for detecting regions of CpG methylation on the basis of the increased melting temperature of methylated DNA, termed denaturation analysis of methylation differences (DAMD). Using the DAMD assay, we find common regions of cancer-specific methylation changes in primary medulloblastomas in critical developmental regulatory pathways, including Sonic hedgehog (Shh), Wingless (Wnt), retinoic acid receptor (RAR), and bone morphogenetic protein (BMP). One of the commonly methylated loci is the PTCH1-1C promoter, a negative regulator of the Shh pathway that is methylated in both primary patient samples and human medulloblastoma cell lines. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) increases the expression of PTCH1 and other methylated loci. Whereas genetic mutations in PTCH1 have previously been shown to lead to medulloblastoma, our study indicates that epigenetic silencing of PTCH1, and other critical developmental loci, by DNA methylation is a fundamental process of pediatric medulloblastoma formation. This finding warrants strong consideration for DNA demethylating agents in future clinical trials for children with this disease.
authors: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Scott J
authors: SJ
authors: Diede
authors: Jamie
authors: J
authors: Guenthoer
authors: Linda N
authors: LN
authors: Geng
authors: Sarah E
authors: SE
authors: Mahoney
authors: Michael
authors: M
authors: Marotta
authors: James M
authors: JM
authors: Olson
authors: Hisashi
authors: H
authors: Tanaka
authors: Stephen J
authors: SJ
authors: Tapscott
mesh_terms: D045744:Cell Line, Tumor; D002648:Child; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D050437:Genes, Developmental; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics*; D046228:Microarray Analysis; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism
chemical_list: C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface