DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer

Katsuhiko Nosho, Kaori Shima, Natsumi Irahara, Shoko Kure, Yoshifumi Baba, Gregory J. Kirkner, Liam Lucian Chen, Sumita Gokhale, Aditi Hazra, Donna Spiegelman, Edward L. Giovannucci, Rudolf Jaenisch, Charles S. Fuchs, Shuji Ogino

Research output: Contribution to journalArticle

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 [≥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, β-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.

Original languageEnglish (US)
Pages (from-to)3663-3671
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number11
DOIs
StatePublished - Jun 1 2009
Externally publishedYes

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CpG Islands
Colorectal Neoplasms
Phenotype
Methylation
Long Interspersed Nucleotide Elements
Microsatellite Instability
Odds Ratio
DNA methyltransferase 3B
Confidence Intervals
Catenins
DNA Methylation
Colonic Neoplasms
Real-Time Polymerase Chain Reaction
Neoplasms
Colon
Cohort Studies
Research Design
Logistic Models
Immunohistochemistry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Nosho, K., Shima, K., Irahara, N., Kure, S., Baba, Y., Kirkner, G. J., ... Ogino, S. (2009). DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer. Clinical Cancer Research, 15(11), 3663-3671. https://doi.org/10.1158/1078-0432.CCR-08-2383

DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer. / Nosho, Katsuhiko; Shima, Kaori; Irahara, Natsumi; Kure, Shoko; Baba, Yoshifumi; Kirkner, Gregory J.; Chen, Liam Lucian; Gokhale, Sumita; Hazra, Aditi; Spiegelman, Donna; Giovannucci, Edward L.; Jaenisch, Rudolf; Fuchs, Charles S.; Ogino, Shuji.

In: Clinical Cancer Research, Vol. 15, No. 11, 01.06.2009, p. 3663-3671.

Research output: Contribution to journalArticle

Nosho, K, Shima, K, Irahara, N, Kure, S, Baba, Y, Kirkner, GJ, Chen, LL, Gokhale, S, Hazra, A, Spiegelman, D, Giovannucci, EL, Jaenisch, R, Fuchs, CS & Ogino, S 2009, 'DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer', Clinical Cancer Research, vol. 15, no. 11, pp. 3663-3671. https://doi.org/10.1158/1078-0432.CCR-08-2383
Nosho, Katsuhiko ; Shima, Kaori ; Irahara, Natsumi ; Kure, Shoko ; Baba, Yoshifumi ; Kirkner, Gregory J. ; Chen, Liam Lucian ; Gokhale, Sumita ; Hazra, Aditi ; Spiegelman, Donna ; Giovannucci, Edward L. ; Jaenisch, Rudolf ; Fuchs, Charles S. ; Ogino, Shuji. / DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 11. pp. 3663-3671.
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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 [≥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, β-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.",
author = "Katsuhiko Nosho and Kaori Shima and Natsumi Irahara and Shoko Kure and Yoshifumi Baba and Kirkner, {Gregory J.} and Chen, {Liam Lucian} and Sumita Gokhale and Aditi Hazra and Donna Spiegelman and Giovannucci, {Edward L.} and Rudolf Jaenisch and Fuchs, {Charles S.} and Shuji Ogino",
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AU - Nosho, Katsuhiko

AU - Shima, Kaori

AU - Irahara, Natsumi

AU - Kure, Shoko

AU - Baba, Yoshifumi

AU - Kirkner, Gregory J.

AU - Chen, Liam Lucian

AU - Gokhale, Sumita

AU - Hazra, Aditi

AU - Spiegelman, Donna

AU - Giovannucci, Edward L.

AU - Jaenisch, Rudolf

AU - Fuchs, Charles S.

AU - Ogino, Shuji

PY - 2009/6/1

Y1 - 2009/6/1

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 [≥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, β-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.

AB - 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 [≥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, β-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.

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