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Genome-wide screen of promoter methylation identifies novel markers in melanoma.
- Source :
-
Genome research [Genome Res] 2009 Aug; Vol. 19 (8), pp. 1462-70. Date of Electronic Publication: 2009 Jun 02. - Publication Year :
- 2009
-
Abstract
- DNA methylation is an important component of epigenetic modifications, which influences the transcriptional machinery aberrant in many human diseases. In this study we present the first genome-wide integrative analysis of promoter methylation and gene expression for the identification of methylation markers in melanoma. Genome-wide promoter methylation and gene expression of eight early-passage human melanoma cell strains were compared with newborn and adult melanocytes. We used linear mixed effect models (LME) in combination with a series of filters based on the localization of promoter methylation relative to the transcription start site, overall promoter CpG content, and differential gene expression to discover DNA methylation markers. This approach identified 76 markers, of which 68 were hyper- and eight hypomethylated (LME, P < 0.05). Promoter methylation and differential gene expression of five markers (COL1A2, NPM2, HSPB6, DDIT4L, MT1G) were validated by sequencing of bisulfite-modified DNA and real-time reverse transcriptase PCR, respectively. Importantly, the incidence of promoter methylation of the validated markers increased moderately in early and significantly in advanced-stage melanomas, using early-passage cell strains and snap-frozen tissues (n = 18 and n = 24, respectively) compared with normal melanocytes and nevi (n = 11 and n = 9, respectively). Our approach allows robust identification of methylation markers that can be applied to other studies involving genome-wide promoter methylation. In conclusion, this study represents the first unbiased systematic effort to determine methylation markers in melanoma and revealed several novel genes regulated by promoter methylation that were not described in cancer cells before.
- Subjects :
- Adaptor Proteins, Signal Transducing
Adult
Aged
Cells, Cultured
Cluster Analysis
Collagen genetics
Collagen Type I
Female
Gene Expression Profiling
Genome, Human genetics
HSP20 Heat-Shock Proteins genetics
Humans
Infant, Newborn
Male
Melanoma pathology
Metallothionein genetics
Middle Aged
Molecular Chaperones genetics
Nuclear Proteins genetics
Nucleoplasmins
Oligonucleotide Array Sequence Analysis methods
Phosphoproteins genetics
Proteins genetics
Reproducibility of Results
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, DNA
Tumor Cells, Cultured
Biomarkers, Tumor genetics
DNA Methylation
Genome-Wide Association Study methods
Melanoma genetics
Promoter Regions, Genetic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1088-9051
- Volume :
- 19
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Genome research
- Publication Type :
- Academic Journal
- Accession number :
- 19491193
- Full Text :
- https://doi.org/10.1101/gr.091447.109