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The CpG island methylator phenotype correlates with long-range epigenetic silencing in colorectal cancer.
Mol Cancer Res. 2008 Apr; 6(4):585-91.MC

Abstract

The CpG island methylator phenotype (CIMP), characterized by an exceptionally high frequency of methylation of discrete CpG islands, is observed in 18% to 25% of sporadic colorectal cancers. Another hypermethylation pattern found in colorectal cancers, termed long-range epigenetic silencing, is associated with DNA/histone methylation in three distinct gene clusters at chromosome 2q14.2, showing that DNA hypermethylation can span larger chromosomal domains and lead to the silencing of flanking, unmethylated genes. We investigated whether these two phenotypes are interrelated in colorectal cancers. The CIMP status of 148 sporadic colorectal cancers was determined by methylation-specific PCR. We determined the BRAF V600E mutation by mutant allele-specific PCR amplification. The methylation status of the MLH1 gene and of three CpG islands (EN1, SCTR, and INHBB), corresponding to three distinct clusters along 2q14.2, was determined by methylation-specific PCR. The average number of sites showing methylation in CIMP+ tumors was 2.21, compared with 1.22 for CIMP- individuals, and this difference was highly significant (P = 3.6 x 10(-8), Mann-Whitney test). Moreover, all CIMP+ tumors showed hypermethylation of at least one of these loci, in contrast to CIMP- tumors, where 18 (16%) samples remained unmethylated. The mean number of simultaneously hypermethylated CpG islands at 2q14.2 differs significantly between CIMP- and CIMP+ tumors, suggesting varying effects of domain silencing in this region. Given that the number of hypermethylated loci at 2q14.2 likely affects the range of silenced flanking genes, high frequency of simultaneous hypermethylation of three CpG islands (EN1, SCTR, and INHBB) may have potential influence on specific characteristics of CIMP+ colorectal cancers.

Authors+Show Affiliations

Departament of Genetics, Wroclaw Medical University, ul. Marcinkowskiego 1, 50-368 Wroclaw, Poland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18403637

Citation

Karpinski, Pawel, et al. "The CpG Island Methylator Phenotype Correlates With Long-range Epigenetic Silencing in Colorectal Cancer." Molecular Cancer Research : MCR, vol. 6, no. 4, 2008, pp. 585-91.
Karpinski P, Ramsey D, Grzebieniak Z, et al. The CpG island methylator phenotype correlates with long-range epigenetic silencing in colorectal cancer. Mol Cancer Res. 2008;6(4):585-91.
Karpinski, P., Ramsey, D., Grzebieniak, Z., Sasiadek, M. M., & Blin, N. (2008). The CpG island methylator phenotype correlates with long-range epigenetic silencing in colorectal cancer. Molecular Cancer Research : MCR, 6(4), 585-91. https://doi.org/10.1158/1541-7786.MCR-07-2158
Karpinski P, et al. The CpG Island Methylator Phenotype Correlates With Long-range Epigenetic Silencing in Colorectal Cancer. Mol Cancer Res. 2008;6(4):585-91. PubMed PMID: 18403637.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The CpG island methylator phenotype correlates with long-range epigenetic silencing in colorectal cancer. AU - Karpinski,Pawel, AU - Ramsey,David, AU - Grzebieniak,Zygmunt, AU - Sasiadek,Maria M, AU - Blin,Nikolaus, PY - 2008/4/12/pubmed PY - 2008/7/8/medline PY - 2008/4/12/entrez SP - 585 EP - 91 JF - Molecular cancer research : MCR JO - Mol Cancer Res VL - 6 IS - 4 N2 - The CpG island methylator phenotype (CIMP), characterized by an exceptionally high frequency of methylation of discrete CpG islands, is observed in 18% to 25% of sporadic colorectal cancers. Another hypermethylation pattern found in colorectal cancers, termed long-range epigenetic silencing, is associated with DNA/histone methylation in three distinct gene clusters at chromosome 2q14.2, showing that DNA hypermethylation can span larger chromosomal domains and lead to the silencing of flanking, unmethylated genes. We investigated whether these two phenotypes are interrelated in colorectal cancers. The CIMP status of 148 sporadic colorectal cancers was determined by methylation-specific PCR. We determined the BRAF V600E mutation by mutant allele-specific PCR amplification. The methylation status of the MLH1 gene and of three CpG islands (EN1, SCTR, and INHBB), corresponding to three distinct clusters along 2q14.2, was determined by methylation-specific PCR. The average number of sites showing methylation in CIMP+ tumors was 2.21, compared with 1.22 for CIMP- individuals, and this difference was highly significant (P = 3.6 x 10(-8), Mann-Whitney test). Moreover, all CIMP+ tumors showed hypermethylation of at least one of these loci, in contrast to CIMP- tumors, where 18 (16%) samples remained unmethylated. The mean number of simultaneously hypermethylated CpG islands at 2q14.2 differs significantly between CIMP- and CIMP+ tumors, suggesting varying effects of domain silencing in this region. Given that the number of hypermethylated loci at 2q14.2 likely affects the range of silenced flanking genes, high frequency of simultaneous hypermethylation of three CpG islands (EN1, SCTR, and INHBB) may have potential influence on specific characteristics of CIMP+ colorectal cancers. SN - 1541-7786 UR - https://www.unboundmedicine.com/medline/citation/18403637/The_CpG_island_methylator_phenotype_correlates_with_long_range_epigenetic_silencing_in_colorectal_cancer_ L2 - http://mcr.aacrjournals.org/cgi/pmidlookup?view=long&pmid=18403637 DB - PRIME DP - Unbound Medicine ER -