DNMT3B Expression Might Contribute to CpG Island Methylator Phenotype in Colorectal Cancer Export

@article{citeulike:4715646, abstract = {Purpose: DNA methyltransferase-3B (DNMT3B) plays an important role in de novo CpG island methylation. Dnmt3b can induce colon tumor in mice with methylation in specific CpG islands. We hypothesized that cellular DNMT3B level might influence the occurrence of widespread CpG island methylation (i.e., the CpG island methylator phenotype, CIMP) in colon cancer. Experimental Design: Utilizing 765 colorectal cancers in two cohort studies, we detected DNMT3B expression in 116 (15\%) tumors by immunohistochemistry. We assessed microsatellite instability, quantified DNA methylation in repetitive long interspersed nucleotide element-1 (LINE-1) by Pyrosequencing, eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by real-time PCR (MethyLight). Results: Tumoral DNMT3B overexpression was significantly associated with CIMP-high [[\&ge;]6/8 methylated CIMP-specific promoters; odds ratio (OR), 3.34; 95\% confidence interval, 2.11-5.29; P < 0.0001]. The relations between DNMT3B and methylation in 16 individual CpG islands varied substantially (OR, 0.80-2.96), suggesting variable locus-to-locus specificities of DNMT3B activity. DNMT3B expression was not significantly related with LINE-1 hypomethylation. In multivariate logistic regression, the significant relation between DNMT3B and CIMP-high persisted (OR, 2.39; 95\% confidence interval, 1.11-5.14; P = 0.026) after adjusting for clinical and other molecular features, including p53, {beta}-catenin, LINE-1, microsatellite instability, KRAS, PIK3CA, and BRAF. DNMT3B expression was unrelated with patient outcome, survival, or prognosis. Conclusions: Tumoral DNMT3B overexpression is associated with CIMP-high in colorectal cancer. Our data support a possible role of DNMT3B in nonrandom de novo CpG island methylation leading to colorectal cancer. 10.1158/1078-0432.CCR-08-2383}, author = {Nosho, Katsuhiko and Shima, Kaori and Irahara, Natsumi and Kure, Shoko and Baba, Yoshifumi and Kirkner, Gregory J. and Chen, Li and Gokhale, Sumita and Hazra, Aditi and Spiegelman, Donna and Giovannucci, Edward L. and Jaenisch, Rudolf and Fuchs, Charles S. and Ogino, Shuji}, citeulike-article-id = {4715646}, citeulike-linkout-0 = {http://dx.doi.org/10.1158/1078-0432.CCR-08-2383}, citeulike-linkout-1 = {http://clincancerres.aacrjournals.org/cgi/content/abstract/15/11/3663?etoc}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19470733}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19470733}, day = {1}, doi = {10.1158/1078-0432.CCR-08-2383}, journal = {Clin Cancer Res}, keywords = {cimp, colon, dnmt, epigenetics, gene\_specific\_methylation, global, methylation}, month = {June}, number = {11}, pages = {3663--3671}, posted-at = {2009-06-02 07:41:20}, priority = {2}, title = {DNMT3B Expression Might Contribute to CpG Island Methylator Phenotype in Colorectal Cancer}, url = {http://dx.doi.org/10.1158/1078-0432.CCR-08-2383}, volume = {15}, year = {2009} }

TY - JOUR ID - citeulike:4715646 L3 - citeulike-article-id:4715646 N2 - Purpose: DNA methyltransferase-3B (DNMT3B) plays an important role in de novo CpG island methylation. Dnmt3b can induce colon tumor in mice with methylation in specific CpG islands. We hypothesized that cellular DNMT3B level might influence the occurrence of widespread CpG island methylation (i.e., the CpG island methylator phenotype, CIMP) in colon cancer. Experimental Design: Utilizing 765 colorectal cancers in two cohort studies, we detected DNMT3B expression in 116 (15%) tumors by immunohistochemistry. We assessed microsatellite instability, quantified DNA methylation in repetitive long interspersed nucleotide element-1 (LINE-1) by Pyrosequencing, eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by real-time PCR (MethyLight). Results: Tumoral DNMT3B overexpression was significantly associated with CIMP-high [[&ge;]6/8 methylated CIMP-specific promoters; odds ratio (OR), 3.34; 95% confidence interval, 2.11-5.29; P < 0.0001]. The relations between DNMT3B and methylation in 16 individual CpG islands varied substantially (OR, 0.80-2.96), suggesting variable locus-to-locus specificities of DNMT3B activity. DNMT3B expression was not significantly related with LINE-1 hypomethylation. In multivariate logistic regression, the significant relation between DNMT3B and CIMP-high persisted (OR, 2.39; 95% confidence interval, 1.11-5.14; P = 0.026) after adjusting for clinical and other molecular features, including p53, {beta}-catenin, LINE-1, microsatellite instability, KRAS, PIK3CA, and BRAF. DNMT3B expression was unrelated with patient outcome, survival, or prognosis. Conclusions: Tumoral DNMT3B overexpression is associated with CIMP-high in colorectal cancer. Our data support a possible role of DNMT3B in nonrandom de novo CpG island methylation leading to colorectal cancer. 10.1158/1078-0432.CCR-08-2383 IS - 11 JF - Clin Cancer Res EP - 3671 TI - DNMT3B Expression Might Contribute to CpG Island Methylator Phenotype in Colorectal Cancer VL - 15 SP - 3663 KW - cimp KW - colon KW - dnmt KW - epigenetics KW - gene_specific_methylation KW - global KW - methylation AU - Nosho, Katsuhiko AU - Shima, Kaori AU - Irahara, Natsumi AU - Kure, Shoko AU - Baba, Yoshifumi AU - Kirkner, Gregory AU - Chen, Li AU - Gokhale, Sumita AU - Hazra, Aditi AU - Spiegelman, Donna AU - Giovannucci, Edward AU - Jaenisch, Rudolf AU - Fuchs, Charles AU - Ogino, Shuji PY - 2009/06/01/ UR - http://dx.doi.org/10.1158/1078-0432.CCR-08-2383 ER -