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Reduced folate carrier-1 G80a gene polymorphism is associated with neuroblastoma’s development

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Abstract

Neuroblastoma is a malignant embryonal tumor of neural crest cells that give rise to the sympathetic nervous system, responsible for 10–70 % of all cases of childhood cancer. Because of its early appearance, it has been suggested that risk factors active in the prenatal can be associated with the pathogenesis of neuroblastoma. The aim of this study was to investigate whether the genetic polymorphisms MTHFR C677T and A1298C, MTR A2756G, TYMS 2R/3R and SLC19A1 G80A, involved in folate metabolism, increase the risk of neuroblastoma in Brazilian children. This study comprised 31 Brazilian children (0–14 years old) diagnosed with neuroblastoma compared with 92 controls. Investigation of polymorphisms MTHFR C677T, MTR A2756G and SLC19A1 A80G was performed using PCR–RFLP, the TYMS 2R/3R using PCR and MTHFR A1298C using AS-PCR. The SLC19A1 A80A genotype was significantly associated with the development of neuroblastoma, compared with the control group (Williams G-Test = 0.0286; OR = 5.1667; 95 % CI = 1.4481–18.4338; p = 0.0175). When analyzed together, the 80AG+AA genotypes showed a trend toward association (OR = 3.3033; 95 % CI = 1.0586–10.3080; p = 0.0563). Our results suggest that individuals carriers of genotype AA for the SLC19A1 gene present risk for the development of neuroblastoma and possibly have difficulty in absorption of folic acid by the cells, and this may adversely affect the metabolism of folate causing genomic instability and promoting the development of cancer. This is the first retrospective/prospective study to examine the relationship between polymorphisms of folate pathway genes and risk of neuroblastoma.

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References

  1. Brodeur GM (2003) Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3:203–216

    Article  CAS  PubMed  Google Scholar 

  2. Schwab M, Westermann F, Hero B et al (2003) Neuroblastoma: biology and molecular and chromosomal pathology. Lanc Oncol 4:472–480

    Article  CAS  Google Scholar 

  3. Lam WA, Cao L, Umesh V et al (2010) Extracellular matrix rigidity modulates neuroblastoma cell differentiation and N-myc expression. Mol Cancer 9:35

    Article  PubMed Central  PubMed  Google Scholar 

  4. Gurney JG, Ross JA, Wall DA et al (1997) Infant cancer in the U.S.: histology-specific incidence and trends, 1973 to 1992. J Pediatr Hematol Oncol 19:428–432

    Article  CAS  PubMed  Google Scholar 

  5. Brodeur GM, Maris JM (2002) Neuroblastoma. In: Pizzo PA, Poplack DG (eds) Principles and practice of pediatric oncology, 4th edn. Williams & Wilkins, Philadelphia, pp 865–937

    Google Scholar 

  6. Harder T, Plagemann A, Harder A (2010) Birth weight and risk of neuroblastoma: a meta-analysis. Int J Epidemiol 9(39):746–756

    Article  Google Scholar 

  7. Bailey LB, Gregory JF (1999) Folate metabolism and requirements. J Nut 129:779–782

    CAS  Google Scholar 

  8. Suh JR, Herbig AK, Stover PJ (2001) New perspectives on folate catabolism. Annu Rev Nutr 21:255–282

    Article  CAS  PubMed  Google Scholar 

  9. Doll R (1992) The lessons of life: keynote address to the nutrition and cancer conference. Cancer Res 52:2024–2029

    Google Scholar 

  10. French AE, Grant R, Weitzman S et al (2003) Folic acid food fortification is associated with a decline in neuroblastoma. Clin Pharmacol Ther 74(3):288–294

    Article  CAS  PubMed  Google Scholar 

  11. Sharp L, Little J (2004) Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a huge review. Am J Epidemiol 159:423–443

    Article  PubMed  Google Scholar 

  12. Reeves SG, Meldrum C, Groombridge C et al (2009) MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer. Eur J Human Genet 17:629–635

    Article  CAS  Google Scholar 

  13. Sirachainan N, Wongruangsri S, Kajanachumpol S (2008) Folate pathway genetic polymorphisms and susceptibility of central nervous system tumors in Thai children. Cancer Detect Prev 32:72–78

    Article  CAS  PubMed  Google Scholar 

  14. Lima ELS, Silva VC, Silva HDA et al (2010) MTR polymorphic variant A2756G and retinoblastoma risk in Brazilian children. Pediatr Blood Cancer 54:904–908

    PubMed  Google Scholar 

  15. Ulrich CM, Curtin K, Potter JD et al (2005) Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer. Cancer Epidem Biomar 14:2509–2516

    Article  CAS  Google Scholar 

  16. Chango A, Emery-Fillon N, Courcy GP et al (2000) A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol Genet Metab 70:310–315

    Article  CAS  PubMed  Google Scholar 

  17. Van Der Put NMJ, Van Der Molen EF, Kluijtmans LA et al (1997) Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinemia in neural-tube defects and vascular disease. QJM 90:511–517

    Article  PubMed  Google Scholar 

  18. Frosst P, Blom HJ, Milos R et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113

    Article  CAS  PubMed  Google Scholar 

  19. Van Der Put NMJ, Gabreëls F, Stevens EMB et al (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62:1044–1051

    Article  PubMed Central  PubMed  Google Scholar 

  20. Kawakami K, Omura K, Kanehira E et al (1999) Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 19:3249–3252

    CAS  PubMed  Google Scholar 

  21. Blount BC, Mack MM, Wehr CM 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  PubMed Central  CAS  PubMed  Google Scholar 

  22. Rhys CM, Bohr VA (1996) Mammalian DNA repair responses and genomic instability. EXE 77:289–305

    Google Scholar 

  23. Usmani BA (1993) Genomic instability and metastatic progression. Pathobiol 61:109–116

    Article  CAS  Google Scholar 

  24. Sambrook J, Russel DW (2001) Rapid isolation of yeast DNA. In: Hoffman CS (ed) Molecular cloning, a laboratory manual. Cold Spring Harbor Laboratory, New York, pp 631–632

    Google Scholar 

  25. Nascimento EM, Spinelli MO, Rodrigues CJ et al (2003) Protocolo da extração de DNA de material parafinado para análise de microssatélites em leiomioma. J Bras Patol Med Lab 39(3):253–255

    Article  CAS  Google Scholar 

  26. Biselli JM, Goloni-Bertollo EM, Haddad R et al (2008) The MTR A2756G polymorphism is associated with an increase of plasma homocysteine concentration in Brazilian individuals with down syndrome. Braz J Med Biol Res 41(1):34–40

    Article  CAS  PubMed  Google Scholar 

  27. Harmon DL, Shields DC, Woodside JV et al (1999) Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. Genet Epidemiol 17:298–309

    Article  CAS  PubMed  Google Scholar 

  28. Hishida A, Matsuo K, Hamajima N et al (2003) Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma. Haematol 88:159–166

    CAS  Google Scholar 

  29. Davis SS, Rogers MA, Pendergrass TW (1987) The incidence and epidemiologic characteristics of neuroblastoma in the US. Am J Epidemiol 126:1063–1074

    CAS  PubMed  Google Scholar 

  30. Grovas A, Fremgen A, Rauck A et al (1997) The National Cancer Data Base report on patterns of childhood cancers in the US. Cancer 80:2321–2332

    Article  CAS  PubMed  Google Scholar 

  31. Matherly LH, Hou Z, Deng Y (2007) Human reduced folate carrier: translation of basic biology to cancer etiology and therapy. Cancer Metast Rev 26:111–128

    Article  CAS  Google Scholar 

  32. Whetstine JR, Gifford AJ, Witt T et al (2001) Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His [27] and Arg [27] carriers. Clin Cancer Res 7:3416–3422

    CAS  PubMed  Google Scholar 

  33. De Marco P, Calevo MG, Moroni A et al (2001) Polymorphisms in genes involved in folate metabolism as risk factors for NTDs. Eur J Pediatr Surg 11:S14–S17

    Article  PubMed  Google Scholar 

  34. Shaw GM, Lammer EJ, Zhu H et al (2002) Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida. Am J Med Genet 108:1–6

    Article  PubMed  Google Scholar 

  35. Morin I, Devlin AM, Leclerc D et al (2003) Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk. Mol Genet Metab 79:197–200

    Article  CAS  PubMed  Google Scholar 

  36. Pei L, Zhu H, Ren A et al (2005) Reduced folate carrier gene is a risk factor for neural tube defects in a Chinese population, birth defects. Res A Clin Mol Teratol 73:430–433

    Article  CAS  Google Scholar 

  37. Li J, Shi Y, Sun J et al (2011) Xenopus reduced folate carrier regulates neural crest development epigenetically. PLoS ONE 6:e27198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Wang L, Chen W, Wang J et al (2006) Reduced folate carrier gene G80A polymorphism is associated with an increased risk of gastroesophageal cancers in a chinese population. Eur J Cancer 42:3206–3211

    Article  CAS  PubMed  Google Scholar 

  39. Skibola CF, Forrest MS, Coppede F et al (2004) Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Blood 104:2155–2162

    Article  CAS  PubMed  Google Scholar 

  40. Laverdiere C, Chiasson S, Costea I et al (2002) Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood 100:3832–3834

    Article  PubMed  Google Scholar 

  41. Antony AC (2007) In utero physiology: role of folic acid in nutrient delivery and fetal development. Am J Clin Nutr 85:598S–603S

    CAS  PubMed  Google Scholar 

  42. Ashworth CJ, Antipatis C (2001) Micronutrient programming of development throughout gestation. Reprod 122:527–535

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank the members of the Centro Oncohematológico Pediátrico do Hospital Universitário Oswaldo Cruz da Universidade de Pernambuco, Laboratório de Genética Molecular Humana da Universidade Federal de Pernambuco and the little patients who had participated in this study. Our acknowledgments to Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco (FACEPE) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

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The authors report no conflict of interest.

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Authors and Affiliations

  1. Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica (CEONHPE), Hospital Universitário Oswaldo Cruz – HUOC/UPE, Universidade de Pernambuco – UPE, Arnóbio Marques, 310 - Santo Amaro, Recife, 50100-130, Pernambuco, Brazil

    Dyego O. de Miranda, Jemima E. X. S. Barros, Maria Madalena S. Vieira, Elker L. S. Lima, Vera L. L. Moraes, Helker A. da Silva, Cássia A. Lima, Adriana V. Gomes & Maria T. C. Muniz

  2. Instituto de Ciências Biológicas – ICB, Universidade de Pernambuco – UPE, Arnóbio Marques Street, 310, Santo Amaro- Recife, PE, 50100-130, Brazil

    Dyego O. de Miranda, Adriana V. Gomes & Maria T. C. Muniz

  3. Departamento de Genética, Universidade Federal de Pernambuco – UFPE, Cidade Universitari, Brazil

    Jemima E. X. S. Barros & Helker A. da Silva

  4. Faculdade de Ciências Médicas – FCM, Universidade de Pernambuco – UPE, Santo Amaro, Brazil

    Maria Madalena S. Vieira, Cássia A. Lima, Adriana V. Gomes, Neide Santos & Maria T. C. Muniz

  5. Campus Petrolina – Universidade de Pernambuco – UPE, Petrolina, Brazil

    Helker A. da Silva

  6. Fundação Getúlio Vargas – FGV, Rio de Janeiro, Brazil

    Helder L. B. O. Garcia

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  1. Dyego O. de Miranda
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  2. Jemima E. X. S. Barros
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  3. Maria Madalena S. Vieira
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  4. Elker L. S. Lima
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  5. Vera L. L. Moraes
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  6. Helker A. da Silva
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  7. Helder L. B. O. Garcia
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  8. Cássia A. Lima
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  9. Adriana V. Gomes
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  10. Neide Santos
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  11. Maria T. C. Muniz
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Correspondence to Maria T. C. Muniz.

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de Miranda, D.O., Barros, J.E.X.S., Vieira, M.M.S. et al. Reduced folate carrier-1 G80a gene polymorphism is associated with neuroblastoma’s development. Mol Biol Rep 41, 5069–5075 (2014). https://doi.org/10.1007/s11033-014-3372-6

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  • DOI: https://doi.org/10.1007/s11033-014-3372-6

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