Frequent promoter hypermethylation of Wnt pathway inhibitor genes in malignant astrocytic gliomas
Open Access
- 23 March 2010
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 126 (11), 2584-2593
- https://doi.org/10.1002/ijc.24981
Abstract
Aberrant activation of wingless (Wnt) signaling is involved in the pathogenesis of various cancers. Recent studies suggested a role of Wnt signaling in gliomas, the most common primary brain tumors. We investigated 70 gliomas of different malignancy grades for promoter hypermethylation in 8 genes encoding members of the secreted frizzled-related protein (SFRP1, SFRP2, SFRP4, SFRP5), dickkopf (DKK1, DKK3) and naked (NKD1, NKD2) families of Wnt pathway inhibitors. All tumors were additionally analyzed for mutations in exon 3 of the β-catenin gene (CTNNB1). While none of the tumors carried CTNNB1 mutations, we found frequent promoter hypermethylation of Wnt pathway inhibitor genes, with at least one of these genes being hypermethylated in 6 of 16 diffuse astrocytomas (38%), 4 of 14 anaplastic astrocytomas (29%), 7 of 10 secondary glioblastomas (70%) and 23 of 30 primary glioblastomas (77%). Glioblastomas often demonstrated hypermethylation of 2 or more analyzed genes. Hypermethylation of SFRP1, SFRP2 and NKD2 each occurred in more than 40% of the primary glioblastomas, while DKK1 hypermethylation was found in 50% of secondary glioblastomas. Treatment of SFRP1-, SFRP5-, DKK1-, DKK3-, NKD1- and NKD2-hypermethylated U87-MG glioblastoma cells with 5-aza-2′-deoxycytidine and trichostatin A resulted in increased expression of each gene. Furthermore, SFRP1-hypermethylated gliomas showed significantly lower expression of the respective transcripts when compared with unmethylated tumors. Taken together, our results suggest an important role of epigenetic silencing of Wnt pathway inhibitor genes in astrocytic gliomas, in particular, in glioblastomas, with distinct patterns of hypermethylated genes distinguishing primary from secondary glioblastomas.Keywords
This publication has 42 references indexed in Scilit:
- IDH1andIDH2Mutations in GliomasThe New England Journal of Medicine, 2009
- Correlation of O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT ActivityJournal of Clinical Oncology, 2008
- Wnt signalling and its impact on development and cancerNature Reviews Cancer, 2008
- Long-term survival with glioblastoma multiformeBrain, 2007
- Genetic Pathways to Primary and Secondary GlioblastomaThe American Journal of Pathology, 2007
- The many ways of Wnt in cancerCurrent Opinion in Genetics & Development, 2007
- Population-Based Studies on Incidence, Survival Rates, and Genetic Alterations in Astrocytic and Oligodendroglial GliomasJournal of Neuropathology and Experimental Neurology, 2005
- MGMTGene Silencing and Benefit from Temozolomide in GlioblastomaThe New England Journal of Medicine, 2005
- Primary and secondary glioblastomas: From concept to clinical diagnosisNeuro-Oncology, 1999
- Activation of β-Catenin-Tcf Signaling in Colon Cancer by Mutations in β-Catenin or APCScience, 1997