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

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Abstract

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 MTHFR 429 Ala/Ala and TCN2 259 Arg/Arg and CIMP status in colorectal cancer.

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Abbreviations

BHMT:

Betaine–homocysteine methyltransferase

BMI:

Body mass index

CI:

Confidence interval

CIMP:

CpG island methylator phenotype

HPFS:

Health Professionals Follow-up Study

LINE-1:

Long interspersed nucleotide element-1

MSI:

Microsatellite instability

MTHFR:

Methylenetetrahydrofolate reductase

MTRR:

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

NHS:

Nurses’ Health Study

nsSNP:

Nonsynonymous single nucleotide polymorphism

OR:

Odds ratio

SNP:

Single nucleotide polymorphism

TCN2:

Transcobalamin 2

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Acknowledgments

This research is supported by the National Institutes of Health Research Grants U54 CA100971, P01 CA87969, P01 CA55075, R01 CA070817, P50 CA127003, R03 CA142082, and K07 CA122826 (to S.O.); the Bennett Family Fund; and the Entertainment Industry Foundation’s National Colorectal Cancer Research Alliance. A.H. was supported in part by training grant NIH T-32 CA 09001-30. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the manuscript for publication; or the writing of the manuscript. We deeply thank the Nurses’ Health Study and Health Professionals Follow-up Study cohort participants who generously agreed to provide us with biological specimens and information through responses to questionnaires; hospitals and pathology departments throughout the US for providing us with tumor tissue materials; Walter Willett, Sue Hankinson, and many other staff members who implemented and have maintained the cohort studies; Jean-Pierre Issa, Lanlan Shen, and Liying Yan for their assistance in the LINE-1 Pyrosequencing assay; and Peter Laird and Daniel Weisenberger for their assistance in the MethyLight assay.

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Authors and Affiliations

  1. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA

    Aditi Hazra & David J. Hunter

  2. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA

    Aditi Hazra, Charles S. Fuchs, Gregory J. Kirkner & David J. Hunter

  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA

    Charles S. Fuchs, Takako Kawasaki & Shuji Ogino

  4. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Shuji Ogino

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  1. Aditi Hazra
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Correspondence to Aditi Hazra.

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Hazra, A., Fuchs, C.S., Kawasaki, T. et al. Germline polymorphisms in the one-carbon metabolism pathway and DNA methylation in colorectal cancer. Cancer Causes Control 21, 331–345 (2010). https://doi.org/10.1007/s10552-009-9464-2

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