Cancer Causes & Control

, Volume 21, Issue 3, pp 331–345

Germline polymorphisms in the one-carbon metabolism pathway and DNA methylation in colorectal cancer

  • Aditi Hazra
  • Charles S. Fuchs
  • Takako Kawasaki
  • Gregory J. Kirkner
  • David J. Hunter
  • Shuji Ogino
Original paper

DOI: 10.1007/s10552-009-9464-2

Cite this article as:
Hazra, A., Fuchs, C.S., Kawasaki, T. et al. Cancer Causes Control (2010) 21: 331. doi:10.1007/s10552-009-9464-2


Dietary intake of one-carbon nutrients (methyl donors) and germline variants in the one-carbon metabolism genes may influence global DNA methylation level and methylation in promoter CpG islands. In this study, we evaluated the relationship between single nucleotide polymorphisms (SNPs) in the one-carbon metabolism pathway and DNA methylation status in colorectal cancer. Utilizing 182 colorectal cancers cases in two prospective cohort studies, we determined the CpG island methylator phenotype (CIMP) status on eight CIMP-specific promoters and measured LINE-1 methylation level that correlates well with genome-wide DNA methylation level. We genotyped 23 nonsynonymous SNPs in the one-carbon metabolism genes using buffy coat DNA. Most of the 23 SNPs in the one-carbon metabolism pathway were not significantly associated with CIMP-high status (≥6/8 methylated promoters). However, the MTHFR 429 Ala/Ala variant (rs1801131) and the TCN2 259 Arg/Arg variant (rs1801198) were associated with CIMP-high status (MTHFR 429 multivariate odds ratio (MV OR) = 7.56; 95% confidence interval (CI), 1.32–43.3; p trend = 0.10; TCN2 259 Arg/Arg variant MV OR = 3.82; 95% CI, 1.02–14.4; p trend = 0.06). The one-carbon metabolism genotypes were not significantly associated with LINE-1 methylation, although there were modest differences in mean LINE-1 methylation levels between certain genotypes. Collectively, these exploratory data provide suggestive evidence for the association of MTHFR429 Ala/Ala and TCN2 259 Arg/Arg and CIMP status in colorectal cancer.


SNP One-carbon metabolism Colorectal cancer CIMP DNA methylation 



Betaine–homocysteine methyltransferase


Body mass index


Confidence interval


CpG island methylator phenotype


Health Professionals Follow-up Study


Long interspersed nucleotide element-1


Microsatellite instability


Methylenetetrahydrofolate reductase


5-Methyltetrahydrofolate–homocysteine methyltransferase reductase (methionine synthase reductase)


Nurses’ Health Study


Nonsynonymous single nucleotide polymorphism


Odds ratio


Single nucleotide polymorphism


Transcobalamin 2

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Aditi Hazra
    • 1
    • 2
  • Charles S. Fuchs
    • 2
    • 3
  • Takako Kawasaki
    • 3
  • Gregory J. Kirkner
    • 2
  • David J. Hunter
    • 1
    • 2
  • Shuji Ogino
    • 3
    • 4
  1. 1.Program in Molecular and Genetic Epidemiology, Department of EpidemiologyHarvard School of Public HealthBostonUSA
  2. 2.Channing Laboratory, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  3. 3.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  4. 4.Department of PathologyBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA

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