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  • Original Article
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Single nucleotide polymorphisms in uracil-processing genes, intake of one-carbon nutrients and breast cancer risk

European Journal of Clinical Nutrition volume 65, pages 683–689 (2011)Cite this article

Subjects

Abstract

Background/Objectives:

The misincorporation of uracil into DNA leads to genomic instability. In a previous study, some of us identified four common single nucleotide polymorphisms (SNPs) in uracil-processing genes (rs2029166 and rs7296239 in SMUG1, rs34259 in UNG and rs4775748 in DUT) that were associated with significantly altered levels of uracil in human DNA. We investigated whether any of these SNPs are associated with an altered risk of developing breast cancer and if one-carbon nutrients intake can modify their effects.

Subjects/Methods:

We genotyped the four SNPs in 1077 cases of incident breast cancer and 1910 age and race-matched controls in the Western New York Exposures and Breast Cancer (WEB) Study and examined associations with breast cancer risk and interactions with intake of folate, vitamins B6 and B12.

Results:

After adjustment for known risk factors for breast cancer, there was increased risk of breast cancer among postmenopausal women who were heterozygous for either of the two SMUG1 SNPs (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.07–1.56) and OR 1.29, 95% CI 1.07–1.55, respectively). Among premenopausal women, increased risk associated with the SMUG1 rs2029166 genotype was limited to those with low folate intake. There were no other interactions with vitamins B6 or B12 intake.

Conclusions:

Our study suggests that the four selected SNPs are not robust determinants of breast cancer risk, but that the two SNPs in SMUG1 might modestly alter the risk of breast cancer. However, the increase in risk among heterozygotes in the two SNPs in SMUG1, which is thought to be the most active glycosylase in vivo, raises the possibility that subtle ‘heterosis’ effects on cancer risk might be produced by these SNPs.

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References

  • Ames BN (1999). Micronutrient deficiencies. A major cause of DNA damage. Ann N Y Acad Sci 889, 87–106.

    Article  CAS  Google Scholar 

  • Ames BN, Wakimoto P (2002). Are vitamin and mineral deficiencies a major cancer risk? Nat Rev Cancer 2, 694–704.

    Article  CAS  Google Scholar 

  • Barnes DE, Lindahl T (2004). Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annu Rev Genet 38, 445–476.

    Article  CAS  Google Scholar 

  • Block G, Hartman AM, Dresser CM, Carroll MD, Gannon J, Gardner L (1986). A data-based approach to diet questionnaire design and testing. Am J Epidemiol 124, 453–469.

    Article  CAS  Google Scholar 

  • Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G et al. (1997). Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA 94, 3290–3295.

    Article  CAS  Google Scholar 

  • Bonner MR, Han D, Nie J, Rogerson P, Vena JE, Muti P et al. (2005). Breast cancer risk and exposure in early life to polycyclic aromatic hydrocarbons using total suspended particulates as a proxy measure. Cancer Epidemiol Biomarkers Prev 14, 53–60.

    CAS  PubMed  Google Scholar 

  • Broderick P, Bagratuni T, Vijayakrishnan J, Lubbe S, Chandler I, Houlston RS (2006). Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition. BMC Cancer 6, 243.

    Article  Google Scholar 

  • Chanson A, Parnell LD, Ciappio ED, Liu Z, Crott JW, Tucker KL et al. (2009). Polymorphisms in uracil-processing genes, but not one-carbon nutrients, are associated with altered DNA uracil concentrations in an urban Puerto Rican population. Am J Clin Nutr 89, 1927–1936.

    Article  CAS  Google Scholar 

  • Choi SW, Mason JB (2000). Folate and carcinogenesis: an integrated scheme. J Nutr 130, 129–132.

    Article  CAS  Google Scholar 

  • Comings DE, MacMurray JP (2000). Molecular heterosis: a review. Mol Genet Metab 71, 19–31.

    Article  CAS  Google Scholar 

  • Crow JF (2008). Mid-century controversies in population genetics. Annu Rev Genet 42, 1–16.

    Article  CAS  Google Scholar 

  • Fenech M (2001). The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat Res 475, 57–67.

    Article  CAS  Google Scholar 

  • Giovannucci E (2002). Epidemiologic studies of folate and colorectal neoplasia: a review. J Nutr 132, 2350S–2355S.

    Article  CAS  Google Scholar 

  • Hao B, Wang H, Zhou K, Li Y, Chen X, Zhou G et al. (2004). Identification of genetic variants in base excision repair pathway and their associations with risk of esophageal squamous cell carcinoma. Cancer Res 64, 4378–4384.

    Article  CAS  Google Scholar 

  • Hung RJ, Hall J, Brennan P, Boffetta P (2005). Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. Am J Epidemiol 162, 925–942.

    Article  Google Scholar 

  • Jang H, Mason JB, Choi SW (2005). Genetic and epigenetic interactions between folate and aging in carcinogenesis. J Nutr 135, 2967S–2971S.

    Article  CAS  Google Scholar 

  • Kapiszewska M, Kalemba M, Wojciech U, Milewicz T (2005). Uracil misincorporation into DNA of leukocytes of young women with positive folate balance depends on plasma vitamin B12 concentrations and methylenetetrahydrofolate reductase polymorphisms. A pilot study. J Nutr Biochem 16, 467–478.

    Article  CAS  Google Scholar 

  • Kavli B, Otterlei M, Slupphaug G, Krokan HE (2007). Uracil in DNA—general mutagen, but normal intermediate in acquired immunity. DNA Repair (Amst) 6, 505–516.

    Article  CAS  Google Scholar 

  • Krokan HE, Drablos F, Slupphaug G (2002). Uracil in DNA—occurrence, consequences and repair. Oncogene 21, 8935–8948.

    Article  CAS  Google Scholar 

  • Mashiyama ST, Hansen CM, Roitman E, Sarmiento S, Leklem JE, Shultz TD et al. (2008). An assay for uracil in human DNA at baseline: effect of marginal vitamin B6 deficiency. Anal Biochem 372, 21–31.

    Article  CAS  Google Scholar 

  • Miao R, Gu H, Liu H, Hu Z, Jin G, Wang H et al. (2008). Tagging single nucleotide polymorphisms in MBD4 are associated with risk of lung cancer in a Chinese population. Lung Cancer 62, 281–286.

    Article  Google Scholar 

  • Mohrenweiser HW, Jones IM (1998). Variation in DNA repair is a factor in cancer susceptibility: a paradigm for the promises and perils of individual and population risk estimation? Mutat Res 400, 15–24.

    Article  CAS  Google Scholar 

  • Salanti G, Southam L, Altshuler D, Ardlie K, Barroso I, Boehnke M et al. (2009). Underlying genetic models of inheritance in established type 2 diabetes associations. Am J Epidemiol 170, 537–545.

    Article  Google Scholar 

  • Shin MC, Lee SJ, Choi JE, Cha SI, Kim CH, Lee WK et al. (2006). Glu346Lys polymorphism in the methyl-CpG binding domain 4 gene and the risk of primary lung cancer. Jpn J Clin Oncol 36, 483–488.

    Article  Google Scholar 

  • Sousa MM, Krokan HE, Slupphaug G (2007). DNA-uracil and human pathology. Mol Aspects Med 28, 276–306.

    Article  CAS  Google Scholar 

  • Tao MH, Shields PG, Nie J, Millen A, Ambrosone CB, Edge SB et al. (2009). DNA hypermethylation and clinicopathological features in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study. Breast Cancer Res Treat 114, 559–568.

    Article  CAS  Google Scholar 

  • Tennis M, Krishnan S, Bonner M, Ambrosone CB, Vena JE, Moysich K et al. (2006). p53 Mutation analysis in breast tumors by a DNA microarray method. Cancer Epidemiol Biomarkers Prev 15, 80–85.

    Article  CAS  Google Scholar 

  • Visnes T, Doseth B, Pettersen HS, Hagen L, Sousa MM, Akbari M et al. (2009). Uracil in DNA and its processing by different DNA glycosylases. Philos Trans R Soc Lond B Biol Sci 364, 563–568.

    Article  CAS  Google Scholar 

  • Willett WC, Howe GR, Kushi LH (1997). Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr 65, 1220S–1228S.

    Article  CAS  Google Scholar 

  • Xu X, Chen J (2009). One-carbon metabolism and breast cancer: an epidemiological perspective. J Genet Genomics 36, 203–214.

    Article  CAS  Google Scholar 

  • Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD et al. (2003). Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 95, 373–380.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Carcinogenesis, Biomarkers and Epidemiology Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    C Marian, D S Goerlitz & P G Shields

  2. Department of Social and Preventive Medicine, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, NY, USA

    M Tao, J Nie & J L Freudenheim

  3. Vitamins & Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA

    J B Mason & A Chanson

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  1. C Marian
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  2. M Tao
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  3. J B Mason
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  4. D S Goerlitz
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  5. J Nie
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  6. A Chanson
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  7. J L Freudenheim
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  8. P G Shields
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Correspondence to C Marian.

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Marian, C., Tao, M., Mason, J. et al. Single nucleotide polymorphisms in uracil-processing genes, intake of one-carbon nutrients and breast cancer risk. Eur J Clin Nutr 65, 683–689 (2011). https://doi.org/10.1038/ejcn.2011.29

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