Association of the colorectal CpG island methylator phenotype with molecular features, risk factors, and family history

Daniel J. Weisenberger, A. Joan Levine, Tiffany I. Long, Daniel D. Buchanan, Rhiannon Walters, Mark Clendenning, Christophe Rosty, Amit D. Joshi, Mariana C. Stern, Loic Le Marchand, Noralane Morey Lindor, Darshana Daftary, Steven Gallinger, Teresa Selander, Bharati Bapat, Polly A. Newcomb, Peter T. Campbell, Graham Casey, Dennis J. Ahnen, John A. BaronRobert W. Haile, John L. Hopper, Joanne P. Young, Peter W. Laird, Kimberly D. Siegmund

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case-case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case-case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P < 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5-2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0-5.5), and family history of CRC (ccOR= 0.6; 95% CI, 0.5-0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (P<inf>trend</inf> < 0.001) and body mass index (BMI; P<inf>trend</inf> = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation-based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer.

Original languageEnglish (US)
Pages (from-to)512-519
Number of pages8
JournalCancer Epidemiology Biomarkers and Prevention
Volume24
Issue number3
DOIs
StatePublished - Mar 1 2015

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CpG Islands
Colorectal Neoplasms
Phenotype
Odds Ratio
Environmental Exposure
Neoplasms
Islands
Molecular Epidemiology
DNA Methylation
Colonic Neoplasms
Registries
Life Style
Obesity
Logistic Models
Smoking
Mutation
DNA

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Weisenberger, D. J., Levine, A. J., Long, T. I., Buchanan, D. D., Walters, R., Clendenning, M., ... Siegmund, K. D. (2015). Association of the colorectal CpG island methylator phenotype with molecular features, risk factors, and family history. Cancer Epidemiology Biomarkers and Prevention, 24(3), 512-519. https://doi.org/10.1158/1055-9965.EPI-14-1161

Association of the colorectal CpG island methylator phenotype with molecular features, risk factors, and family history. / Weisenberger, Daniel J.; Levine, A. Joan; Long, Tiffany I.; Buchanan, Daniel D.; Walters, Rhiannon; Clendenning, Mark; Rosty, Christophe; Joshi, Amit D.; Stern, Mariana C.; Le Marchand, Loic; Lindor, Noralane Morey; Daftary, Darshana; Gallinger, Steven; Selander, Teresa; Bapat, Bharati; Newcomb, Polly A.; Campbell, Peter T.; Casey, Graham; Ahnen, Dennis J.; Baron, John A.; Haile, Robert W.; Hopper, John L.; Young, Joanne P.; Laird, Peter W.; Siegmund, Kimberly D.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 24, No. 3, 01.03.2015, p. 512-519.

Research output: Contribution to journalArticle

Weisenberger, DJ, Levine, AJ, Long, TI, Buchanan, DD, Walters, R, Clendenning, M, Rosty, C, Joshi, AD, Stern, MC, Le Marchand, L, Lindor, NM, Daftary, D, Gallinger, S, Selander, T, Bapat, B, Newcomb, PA, Campbell, PT, Casey, G, Ahnen, DJ, Baron, JA, Haile, RW, Hopper, JL, Young, JP, Laird, PW & Siegmund, KD 2015, 'Association of the colorectal CpG island methylator phenotype with molecular features, risk factors, and family history', Cancer Epidemiology Biomarkers and Prevention, vol. 24, no. 3, pp. 512-519. https://doi.org/10.1158/1055-9965.EPI-14-1161
Weisenberger, Daniel J. ; Levine, A. Joan ; Long, Tiffany I. ; Buchanan, Daniel D. ; Walters, Rhiannon ; Clendenning, Mark ; Rosty, Christophe ; Joshi, Amit D. ; Stern, Mariana C. ; Le Marchand, Loic ; Lindor, Noralane Morey ; Daftary, Darshana ; Gallinger, Steven ; Selander, Teresa ; Bapat, Bharati ; Newcomb, Polly A. ; Campbell, Peter T. ; Casey, Graham ; Ahnen, Dennis J. ; Baron, John A. ; Haile, Robert W. ; Hopper, John L. ; Young, Joanne P. ; Laird, Peter W. ; Siegmund, Kimberly D. / Association of the colorectal CpG island methylator phenotype with molecular features, risk factors, and family history. In: Cancer Epidemiology Biomarkers and Prevention. 2015 ; Vol. 24, No. 3. pp. 512-519.
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abstract = "Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case-case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case-case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P < 0.0001), female sex [ccOR = 1.8; 95{\%} confidence interval (CI), 1.5-2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95{\%} CI, 3.0-5.5), and family history of CRC (ccOR= 0.6; 95{\%} CI, 0.5-0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend < 0.001) and body mass index (BMI; Ptrend = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation-based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer.",
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T1 - Association of the colorectal CpG island methylator phenotype with molecular features, risk factors, and family history

AU - Weisenberger, Daniel J.

AU - Levine, A. Joan

AU - Long, Tiffany I.

AU - Buchanan, Daniel D.

AU - Walters, Rhiannon

AU - Clendenning, Mark

AU - Rosty, Christophe

AU - Joshi, Amit D.

AU - Stern, Mariana C.

AU - Le Marchand, Loic

AU - Lindor, Noralane Morey

AU - Daftary, Darshana

AU - Gallinger, Steven

AU - Selander, Teresa

AU - Bapat, Bharati

AU - Newcomb, Polly A.

AU - Campbell, Peter T.

AU - Casey, Graham

AU - Ahnen, Dennis J.

AU - Baron, John A.

AU - Haile, Robert W.

AU - Hopper, John L.

AU - Young, Joanne P.

AU - Laird, Peter W.

AU - Siegmund, Kimberly D.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case-case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case-case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P < 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5-2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0-5.5), and family history of CRC (ccOR= 0.6; 95% CI, 0.5-0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend < 0.001) and body mass index (BMI; Ptrend = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation-based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer.

AB - Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case-case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case-case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P < 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5-2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0-5.5), and family history of CRC (ccOR= 0.6; 95% CI, 0.5-0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend < 0.001) and body mass index (BMI; Ptrend = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation-based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer.

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