title: DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 [> or =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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Natsumi
authors.initials: N
authors.lastname: Irahara
authors.forename: Shoko
authors.initials: S
authors.lastname: Kure
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kirkner
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Sumita
authors.initials: S
authors.lastname: Gokhale
authors.forename: Aditi
authors.initials: A
authors.lastname: Hazra
authors.forename: Donna
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000368:Aged; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018899:CpG Islands / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015999:Multivariate Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051176:beta Catenin / Q000235:genetics; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D000097584:DNA Methyltransferase 3B