Skip to main content

Advertisement

SpringerLink
Log in

Genetic polymorphisms in the one-carbon metabolism pathway genes and susceptibility to non-Hodgkin lymphoma

  • Research Article
  • Published:
Tumor Biology

Abstract

Corroborating evidence related to the role of aberrations on one-carbon metabolism (OCM) genes has been inconsistent. We evaluated the association between polymorphisms in 12 single nucleotide polymorphisms (SNPs) in 8 OCM genes (CBS, FPGS, FTHFD, MTRR, SHMT1, SLC19A1, TCN1, and TYMS), and non-Hodgkin lymphoma (NHL) risk in a multi-ethnic population which includes Malay, Chinese and Indian ethnic subgroups. Cases (N = 372) and controls (N = 722) were genotyped using the Sequenom MassARRAY platform. Our results of the pooled subjects showed a significantly enhanced NHL risk for CBS Ex9 + 33C > T (T versus C: OR 1.55, 95 % CI 1.22–1.96, P = 0.0003), CBS Ex18-319G > A (A versus G: OR 1.15, 95 % CI 1.14–1.83; P = 0.002), SHMT1 Ex12 + 236 T > C (T versus C: OR 1.44, 95 % CI 1.15–1.81, P = 0.002), and TYMS Ex8 + 157C > T (T versus C: OR 1.29, 95 % CI 1.06–1.57, P = 0.01). Haplotype analysis for CBS SNPs showed a significantly decreased risk of NHL in subjects with haplotype CG (OR 0.69, 95 % CI 0.56–0.86, P = <0.001). The GG haplotype for the FTHFD SNPs showed a significant increased risk of NHL (OR 1.40, 95 % CI 1.12–1.76, P = 0.002). For the TYMS gene, haplotype CAT at TYMS (OR 0.67, 95 % CI 0.49–0.90, P = 0.007) was associated with decreased risk of NHL, while haplotype TAC (OR 1.29, 95 % CI 1.05–1.58, P = 0.01) was found to confer increased risk of NHL. Our study suggests that variation in several OCM genes (CBS, FTHFD, SHMT1, TCN1, and TYMS) may influence susceptibility to NHL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117(19):5019–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. American Cancer Society. Cancer facts & figures 2014. Atlanta: American Cancer Society; 2014.

    Google Scholar 

  3. Alexander DD, Mink PJ, Adami HO, Chang ET, Cole P, Mandel JS, et al. The non-Hodgkin lymphomas: a review of the epidemiologic literature. Int J Cancer. 2007;120 Suppl 12:1–39.

    Article  PubMed  Google Scholar 

  4. Skrabek P, Turner D, Seftel M. Epidemiology of non-Hodgkin lymphoma. Transfus Apher Sci. 2013;49(2):133–8.

    Article  PubMed  Google Scholar 

  5. Boccolini PMM, Boccolini CS, Chrisman JR, Markowitz SB, Koifman S, Koifman RJ, et al. Pesticide use and non-Hodgkin’s lymphoma mortality in Brazil. Int J Hyg Envir Heal. 2013;216(4):461–6.

    Article  CAS  Google Scholar 

  6. Grulich AE, Vajdic CM. The epidemiology of non-Hodgkin lymphoma. Pathology. 2005;37(6):409–19.

    Article  PubMed  Google Scholar 

  7. Bassig BA, Lan Q, Rothman N, Zhang Y, Zheng T. Current understanding of lifestyle and environmental factors and risk of non-Hodgkin lymphoma: an epidemiological update. J Cancer Epidemiol. 2012;2012:978930.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Nauss KM, Newberne PM. Effects of dietary folate, vitamin B12 and methionine/choline deficiency on immune function. Adv Exp Med Biol. 1981;135:63–91.

    CAS  PubMed  Google Scholar 

  9. Koutros S, Zhang Y, Zhu Y, Mayne ST, Zahm SH, Holford TR, et al. Nutrients contributing to one-carbon metabolism and risk of non-Hodgkin lymphoma subtypes. Am J Epidemiol. 2008;167(3):287–94.

    Article  PubMed  Google Scholar 

  10. Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood. 1993;82(6):1820–8.

    CAS  PubMed  Google Scholar 

  11. Rossi D, Capello D, Gloghini A, Franceschetti S, Paulli M, Bhatia K, et al. Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia. Haematologica. 2004;89(2):154–64.

    CAS  PubMed  Google Scholar 

  12. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer. 2005;5(4):251–62.

    Article  PubMed  Google Scholar 

  13. Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011;34(1):75–81.

    Article  CAS  PubMed  Google Scholar 

  14. Metayer C, Scelo G, Chokkalingam AP, Barcellos LF, Aldrich MC, Chang JS, et al. Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia. Cancer Causes Control. 2011;22(9):1243–58.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Osborne CB, Lowe KE, Shane B. Regulation of folate and one-carbon metabolism in mammalian cells. I. Folate metabolism in Chinese hamster ovary cells expressing Escherichia coli or human folylpoly-gamma-glutamate synthetase activity. J Biol Chem. 1993;268(29):21657–64.

    CAS  PubMed  Google Scholar 

  16. Lee KM, Lan Q, Kricker A, Purdue MP, Grulich AE, Vajdic CM, et al. One-carbon metabolism gene polymorphisms and risk of non-Hodgkin lymphoma in Australia. Hum Genet. 2007;122(5):525–33.

    Article  CAS  PubMed  Google Scholar 

  17. Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H, et al. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab. 1999;67(4):317–23.

    Article  CAS  PubMed  Google Scholar 

  18. Girgis S, Suh JR, Jolivet J, Stover PJ. 5-Formyltetrahydrofolate regulates homocysteine remethylation in human neuroblastoma. J Biol Chem. 1997;272(8):4729–34.

    Article  CAS  PubMed  Google Scholar 

  19. Chango A, Emery-Fillon N, de Courcy GP, Lambert D, Pfister M, Rosenblatt DS, et al. A polymorphism (80G- > A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol Genet Metab. 2000;70(4):310–5.

    Article  CAS  PubMed  Google Scholar 

  20. Tanaka T, Scheet P, Giusti B, Bandinelli S, Piras MG, Usala G, et al. Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am J Hum Genet. 2009;84(4):477–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li Q, Lan Q, Zhang Y, Bassig BA, Holford TR, Leaderer B, et al. Role of one-carbon metabolizing pathway genes and gene-nutrient interaction in the risk of non-Hodgkin lymphoma. Cancer Causes Control. 2013;24(10):1875–84.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lim U, Wang SS, Hartge P, Cozen W, Kelemen LE, Chanock S, et al. Gene-nutrient interactions among determinants of folate and one-carbon metabolism on the risk of non-Hodgkin lymphoma: NCI-SEER case- control study. Blood. 2007;109(7):3050–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Gemmati D, Ongaro A, Scapoli GL, Della Porta M, Tognazzo S, Serino ML, et al. Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin’s lymphoma in adults. Cancer Epidemiol Biomarkers Prev. 2004;13(5):787–94.

    CAS  PubMed  Google Scholar 

  24. Christman JK, Sheikhnejad G, Dizik M, Abileah S, Wainfan E. Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency. Carcinogenesis. 1993;14(4):551–7.

    Article  CAS  PubMed  Google Scholar 

  25. Skibola CF, Forrest MS, Coppede F, Agana L, Hubbard A, Smith MT, et al. Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Blood. 2004;104(7):2155–62.

    Article  CAS  PubMed  Google Scholar 

  26. Suthandiram S, Gan GG, Zain SM, Haerian BS, Bee PC, Lian LH et al. Polymorphisms in methylenetetrahydrofolate reductase gene and risk of non-Hodgkin lymphoma in a multi-ethnic population. J Hum Genet. 2014;59(5):280–87.

  27. Jaffe ES (2009) The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology 2009:523–31.

  28. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111–3.

    Article  CAS  PubMed  Google Scholar 

  29. Packer BR, Yeager M, Burdett L, Welch R, Beerman M, Qi L, et al. SNP500Cancer: a public resource for sequence validation, assay development, and frequency analysis for genetic variation in candidate genes. Nucleic Acids Res. 2006;34:D617–21. Database issue.

    Article  CAS  PubMed  Google Scholar 

  30. Shen M, Rothman N, Berndt SI, He X, Yeager M, Welch R, et al. Polymorphisms in folate metabolic genes and lung cancer risk in Xuan Wei, China. Lung Cancer. 2005;49(3):299–309.

    Article  PubMed  Google Scholar 

  31. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57(1):289–300.

    Google Scholar 

  32. Zhou JY, Shi R, Yu HL, Zeng Y, Zheng WL, Ma WL. Association between polymorphic sites in thymidylate synthase gene and risk of non-Hodgkin lymphoma: a systematic review and pooled analysis. Leuk Lymphoma. 2012;53(10):1953–60.

    Article  CAS  PubMed  Google Scholar 

  33. Kim HN, Lee IK, Kim YK, Tran HT, Yang DH, Lee JJ, et al. Association between folate-metabolizing pathway polymorphism and non-Hodgkin lymphoma. Br J Haematol. 2008;140(3):287–94.

    Article  CAS  PubMed  Google Scholar 

  34. Weiner AS, Beresina OV, Voronina EN, Voropaeva EN, Boyarskih UA, Pospelova TI, et al. Polymorphisms in folate-metabolizing genes and risk of non-Hodgkin’s lymphoma. Leuk Res. 2011;35(4):508–15.

    Article  CAS  PubMed  Google Scholar 

  35. Lim U, Weinstein S, Albanes D, Pietinen P, Teerenhovi L, Taylor PR, et al. Dietary factors of one-carbon metabolism in relation to non-Hodgkin lymphoma and multiple myeloma in a cohort of male smokers. Cancer Epidemiol Biomarkers Prev. 2006;15(6):1109–14.

    Article  CAS  PubMed  Google Scholar 

  36. Hishida A, Matsuo K, Hamajima N, Ito H, Ogura M, Kagami Y, et al. Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma. Haematologica. 2003;88(2):159–66.

    CAS  PubMed  Google Scholar 

  37. Lightfoot TJ, Skibola CF, Willett EV, Skibola DR, Allan JM, Coppede F, et al. Risk of non-Hodgkin lymphoma associated with polymorphisms in folate-metabolizing genes. Cancer Epidemiol Biomarkers Prev. 2005;14(12):2999–3003.

    Article  CAS  PubMed  Google Scholar 

  38. Andaya LY. The search for the ‘origin’ of Melayu. J South Asian Stud. 2001;32:315–30.

    Google Scholar 

  39. Tay CY, Mitchell H, Dong Q, Goh KL, Dawes IW, Lan R. Population structure of Helicobacter pylori among ethnic groups in Malaysia: recent acquisition of the bacterium by the Malay population. BMC Microbiol. 2009;9:126.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Di Piazza F. Malaysia in Pictures. Twenty-First Century Books.; 2006

  41. Bamshad M, Kivisild T, Watkins WS, Dixon ME, Ricker CE, Rao BB, et al. Genetic evidence on the origins of Indian caste populations. Genome Res. 2001;11(6):994–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Marchani EE, Watkins WS, Bulayeva K, Harpending HC, Jorde LB. Culture creates genetic structure in the Caucasus: autosomal, mitochondrial, and Y-chromosomal variation in Daghestan. BMC Genet. 2008;9:47.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Reuland SN, Vlasov AP, Krupenko SA. Modular organization of FDH: exploring the basis of hydrolase catalysis. Protein Sci. 2006;15(5):1076–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Krupenko SA, Oleinik NV. 10-formyltetrahydrofolate dehydrogenase, one of the major folate enzymes, is down-regulated in tumor tissues and possesses suppressor effects on cancer cells. Cell Growth Differ. 2002;13(5):227–36.

    CAS  PubMed  Google Scholar 

  45. Anguera MC, Field MS, Perry C, Ghandour H, Chiang EP, Selhub J, et al. Regulation of folate-mediated one-carbon metabolism by 10-formyltetrahydrofolate dehydrogenase. J Biol Chem. 2006;281(27):18335–42.

    Article  CAS  PubMed  Google Scholar 

  46. Hammer MF, Karafet TM, Park H, Omoto K, Harihara S, Stoneking M, et al. Dual origins of the Japanese: common ground for hunter-gatherer and farmer Y chromosomes. J Hum Genet. 2006;51(1):47–58.

    Article  PubMed  Google Scholar 

  47. Liu CH, Ho KL, Hou KC, Lai KF. A new history of Malaysian Chinese, 3 Volume (in Chinese). Kuala Lumpur.: The Federation of Chinese Association Malaysia; 1998.

    Google Scholar 

  48. Chen J, Zheng H, Bei JX, Sun L, Jia WH, Li T, et al. Genetic structure of the Han Chinese population revealed by genome-wide SNP variation. Am J Hum Genet. 2009;85(6):775–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Marchini J, Cardon LR, Phillips MS, Donnelly P. The effects of human population structure on large genetic association studies. Nat Genet. 2004;36(5):512–7.

    Article  CAS  PubMed  Google Scholar 

  50. Hazra A, Kraft P, Lazarus R, Chen C, Chanock SJ, Jacques P, et al. Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway. Hum Mol Genet. 2009;18(23):4677–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A. 1997;94(7):3290–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhao H, Pfeiffer R, Gail MH. Haplotype analysis in population genetics and association studies. Pharmacogenomics. 2003;4(2):171–8.

    Article  PubMed  Google Scholar 

  53. Morton LM, Wang SS, Cozen W, Linet MS, Chatterjee N, Davis S, et al. Etiologic heterogeneity among non-Hodgkin lymphoma subtypes. Blood. 2008;112(13):5150–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the Director of Health Malaysia for permission to publish this paper. The authors gratefully acknowledge the study subjects for their participation in this study and to the staff of UMMC and Ampang Hospital for their assistance in subject recruitment. This study was supported by the HIR MOHE grant E000025-20001, University Malaya Research Grant (UMRG; RG300/11HTM), University Malaya IPPP grant (PV072/2011B) and University Malaya IPPP grant (PS190/2010B).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Sujatha Suthandiram, Shamsul Mohd Zain & Zahurin Mohamed

  2. Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Gin-Gin Gan & Ping-Chong Bee

  3. Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Lay-Hoong Lian

  4. Department of Hematology, Ampang Hospital, Kuala Lumpur, Selangor Darul Ehsan, Malaysia

    Kian-Meng Chang & Tee-Chuan Ong

Authors
  1. Sujatha Suthandiram
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gin-Gin Gan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shamsul Mohd Zain
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ping-Chong Bee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lay-Hoong Lian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kian-Meng Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tee-Chuan Ong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zahurin Mohamed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sujatha Suthandiram.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suthandiram, S., Gan, GG., Zain, S.M. et al. Genetic polymorphisms in the one-carbon metabolism pathway genes and susceptibility to non-Hodgkin lymphoma. Tumor Biol. 36, 1819–1834 (2015). https://doi.org/10.1007/s13277-014-2785-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2785-0

Keywords

Search

Navigation