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MTHFD1 G1958A, BHMT G742A, TC2 C776G and TC2 A67G polymorphisms and head and neck squamous cell carcinoma risk

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Abstract

Alterations in folate metabolism may contribute to the process of carcinogenesis by influencing DNA methylation and genomic stability. Polymorphisms in genes encoding enzymes involved in this pathway may alter enzyme activity and consequently interfere in concentrations of homocysteine and S-adenosylmethionine that are important for DNA synthesis and cellular methylation reactions. The objectives were to investigate MTHFD1 G1958A, BHMT G742A, TC2 C776G and TC2 A67G polymorphisms involved in folate metabolism on head and neck cancer risk and the association between these polymorphisms with risk factors. Polymorphisms were investigated in 762 individuals (272 patients and 490 controls) by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and Real Time-PCR. Chi-square and Multiple logistic regression were used for the statistical analysis. Multiple logistic regression showed that tobacco and male gender were predictors for the disease (P < 0.05). Hardy–Weinberg equilibrium showed that the genotypic distributions were in equilibrium for both groups in all polymorphisms studied. The BHMT 742GA or AA genotypes associated with tobacco consumption (P = 0.016) increase the risk for head and neck squamous cell carcinoma (HNSCC). The present study suggests that BHMT 742GA polymorphism associated to tobacco modulate HNSCC risk. However, further investigation of gene–gene interactions in folate metabolism and studies in different populations are needed to investigate polymorphisms and HNSCC risk.

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References

  1. Marcu LG, Yeoh E (2009) A review of risk factors and genetic alterations in head and neck carcinogenesis and implications for current and future approaches to treatment. J Cancer Res Clin Oncol 135:1303–1314

    PubMed  Google Scholar 

  2. Ragin CCR, Modugno F, Gollin SM (2007) The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus. J Dent Res 86:104–114

    PubMed  CAS  Google Scholar 

  3. Olivieri EHR, da Silva SD, Mendonça FF, Urata YN, Vidal DO, Faria MAM, Nishimoto IN, Rainho CA, Kowalski LP, Rogatto SR (2009) CYP1A2*1C, CYP2E1*5B, and GSTM1 polymorphisms are predictors of risk and poor outcome in head and neck squamous cell carcinoma patients. Oral Oncol 45:73–79

    Google Scholar 

  4. Wang Y, Guo W, He Y, Chen Z, Wen D, Zhang X, Wang N, Li Y, Ge H, Zhang J (2007) Association of MTHFR C677T and SHMT1 C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China. Cancer Causes Control 18:143–152

    PubMed  CAS  Google Scholar 

  5. Wang L, Lu J, An J, Shi Q, Spitz MR, Wei O (2007) Polymorphisms of cytosolic serine hydroxyl-methyltransferase and risk of lung cancer: a case—control analysis. Lung Cancer 57:143–151

    PubMed  Google Scholar 

  6. Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SMT, Motola J Jr, Laginha FM, Tsugane S (2009) Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women. BMC Cancer 9:122

    PubMed  Google Scholar 

  7. Linhart HG, Troen A, Bell GW, Cantu E, Chao W, Moran E, Steine E, He T, Jaenisch R (2009) Folate deficiency induces genomic uracil misincorporation and hypomethylation but does not increase dna point mutations. Gastroenterology 136:227–235

    PubMed  Google Scholar 

  8. Garcia-Crespo D, Knock E, Jabado N, Rozen R (2009) Intestinal neoplasia induced by low dietary folate is associated with altered tumor expression profiles and decreased apoptosis in mouse normal intestine. J Nutr 139:488–494

    PubMed  CAS  Google Scholar 

  9. Langevin SM, Lin D, Matsuo K, Gao CM, Takezaki T, Stolzenberg-Solomon RZ, Vasavi M, Hasan Q, Taioli E (2009) Review and pooled analysis of studies on MTHFR C677T polymorphism and esophageal câncer. Toxicol Lett 184:73–80

    PubMed  CAS  Google Scholar 

  10. Kane MA (2005) The role of folates in squamous cell carcinoma of the head and neck. Cancer Detect Prev 29:46–53

    PubMed  CAS  Google Scholar 

  11. Kim DH (2007) The interactive effect of methyl-group diet and polymorphism of methylenetetrahydrofolate reductase on the risk of colorectal cancer. Mutat Res 622:14–18

    PubMed  CAS  Google Scholar 

  12. Kim YI (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10:66–88

    PubMed  CAS  Google Scholar 

  13. Mason JB, Choi SW (2005) Effects of alcohol on folate metabolism: implications for Carcinogenesis. Alcohol 35:235–241

    PubMed  CAS  Google Scholar 

  14. Xu X, Gammon MD, Wetmur JG, Bradshaw PT, Teitelbaum SL, Neugut AI, Santella RM, Chen J (2008) B-vitamin intake, one-carbon metabolism, and survival in a population based study of women with breast cancer. Cancer Epidemiol Biomarkers Prev 8:2109–2116

    Google Scholar 

  15. Kalmbach RD, Choumenkovitch SF, Troen AP, Jacques PF, D’Agostino R, Selhub J (2008) A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate. J Nutr 138:2323–2327

    PubMed  CAS  Google Scholar 

  16. Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, Johnson KA, Johnson C, Buys SS, Hoover RN, Ziegler RG (2006) Folate intake, alcohol use, and postmenopausal breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Am J Clin Nutr 83:895–904

    PubMed  CAS  Google Scholar 

  17. Xu X, Gammon MD, Zeisel SH, Lee YL, Wetmur JG, Teitelbaum SL, Bradshaw PT, Neugut AI, Santella RM, Chen J (2008) Choline metabolism and risk of breast cancer in a population-based study. FASEB J 22:2045–2052

    PubMed  CAS  Google Scholar 

  18. Hsiung DT, Marsit CJ, Houseman EA, Eddy K, Furniss CS, McClean MD, Kelsey KT (2007) Global DNA methylation level in whole blood as a biomarker in head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 16:108–114

    PubMed  Google Scholar 

  19. Charasson V, Hillaire-Buys D, Solassol I, Laurand-Quancard A, Pinguet F, Morvan VL, Robert J (2009) Involvement of gene polymorphisms of the folate pathway enzymes in gene expression and anticancer drug sensitivity using the NCI-60 panel as a model. Eur J Cancer 45:2391–2401

    PubMed  CAS  Google Scholar 

  20. Krajinovic M, Lemieux-Blanchard E, Chiasson S, Primeau M, Costea I, Moghrabi A (2004) Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 4:66–72

    PubMed  CAS  Google Scholar 

  21. Stevens VL, McCullough ML, Pavluck AL, Talbot JT, Feigelson HS, Thun MJ, Calle EE (2007) Association of polymorphisms in one-carbon metabolism genes and postmenopausal breast cancer incidence. Cancer Epidemiol Biomarkers 16:1140–1147

    CAS  Google Scholar 

  22. Weisberg IS, Park E, Ballman KV, Berger P, Nunn M, Suh DS, Breksa AP 3rd, Garrow TA, Rozen R (2003) Investigations of a common genetic variant in betaine-homocysteine methyltransferase (BHMT) in coronary artery disease. Atherosclerosis 167:205–214

    PubMed  CAS  Google Scholar 

  23. Morin I, Platt R, Weisberg I, Sabbaghian N, Wu Q, Garrow TA, Rozen R (2003) Common variant in betaine-homocysteine methyltransferase (BHMT) and risk for spina bifida. Am J Med Genet 119A:172–176

    PubMed  Google Scholar 

  24. Heil SG, Van der Put NM, Waas ET, den Heijer M, Trijbels FJ, Blom HJ (2001) Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Mol Genet Metab 73:164–172

    PubMed  CAS  Google Scholar 

  25. Zhu H, Curry S, Wen S, Wicker NJ, Shaw GM, Lammer EJ, Yang W, Jafarov T, Finnell RH (2005) Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for Spina Bifida and orofacial clefts? Am J Med Genet 135A:274–277

    Google Scholar 

  26. Koushik A, Kraft P, Fuchs CS, Hankinson SE, Willett WC, Giovannucci EL, Hunter DJ (2006) Nonsynonymous polymorphisms in genes in the one-carbon metabolism pathway and associations with colorectal cancer. Cancer Epidemiol Biomarkers Prev 15:2408–2417

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  28. Afman LA, Lievers KJ, Van der Put NM, Trijbels FJ, Blom HJ (2002) Single nucleotide polymorphisms in the transcobalamin gene: relationship with transcobalamin concentrations and risk for neural tube defects. Eur J Hum Genet 10:433–438

    PubMed  CAS  Google Scholar 

  29. Miller JW, Ramos MI, Garrod MG, Flynn MA, Green R (2002) Transcobalamin II 775GNC polymorphism and indices of vitamin B12 status in healthy older adults. Blood 15:718–720

    Google Scholar 

  30. Biselli JM, Brumati D, Frigeri VF, Zampieri BL, Goloni-Bertollo EM, Pavarino-Bertelli EC (2008) A80G polymorphism of reduced folate carrier 1 (RFC1) and C776G polymorphism of transcobalamin 2 (TC2) genes in Down’s syndrome etiology. Med J 126:329–332

    Google Scholar 

  31. Kjaerhein K, Gaard M, Andersen A (1998) The role of alcohol, tobacco, and dietary factors in upper aerogastric tract cancer: a prospective study of 10.900 Norwegian men. Cancer Causes and Control 9:99–108

    Google Scholar 

  32. Ahrendt SA, Chown JT, Yang SC, Wu L, Zhang MJ, Jen J, Sidransky D (2000) Alcohol comsuption and cigarette smoking increase the frequency of p53 mutations in nonsmall cell lung cancer. Cancer Res 60:3155–3159

    PubMed  CAS  Google Scholar 

  33. Miller SA, Dikes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    PubMed  CAS  Google Scholar 

  34. Hol FA, Van der Put NM, Geurds MP, Heil SG, Trijbels FJ, Hamel BC, Mariman EC, Blom HJ (1998) Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydro-lase, formyltetrahydrofolate synthetase) in patients with neural tube defects. Clin Genet 2:119–125

    Google Scholar 

  35. Pietrzyk JJ, Bik-Multanowski M (2003) 776C > G polymorphism of the transcobalamin II gene as a risk factor for spina bifida. Mol Genet Metab 80:364

    PubMed  CAS  Google Scholar 

  36. Serefoglou Z, Yapijakis C, Nkenke E, Vairaktaris E (2008) Genetic association of cytokine DNA polymorphisms with head and neck cancer. Oral Oncol 44:1093–1099

    PubMed  CAS  Google Scholar 

  37. Canova C, Hashibe M, Simonato L, Nelis M, Metspalu A, Lagiou P, Trichopoulos D, Ahrens W, Pigeot I, Merletti F, Richiard L, Talamini R, Barzan L, Macfarlane GJ, Macfarlane TV, Hocátová I, Bencko V, Benhamou S, Bouchardy C, Kjaerhein K, Lowry R, Agudo A, Castellsagué X, Conway DI, McKinney PA, Znaor A, McCartan BE, Healy CM, Marron M, Brennan P (2009) Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 european countries: the arcage project. Cancer Res 69:2956–2965

    PubMed  CAS  Google Scholar 

  38. Galbiatti ALS, Ruiz MT, Pinto DR, Raposo LS, Maniglia JV, Pavarino-Bertelli EC et al (2010) A80G polymorphism of reduced folate carrier 1 (RFC1) gene and head and neck squamous cell carcinoma etiology in Brazilian population. Mol Biol Rep 38:1071–1078

    PubMed  Google Scholar 

  39. Ishiguro S, Sasazuki S, Inoue M, Kurahashia N, Iwasakia M, Tsugane S (2009) Effect of alcohol consumption, cigarette smoking and flushing response on esophageal cancer risk: A population-based cohort study (JPHC study). Cancer Lett 275:240–246

    PubMed  CAS  Google Scholar 

  40. Argiris A, Karamouzis MV, Raben D, Ferris RL (2008) Head and neck cancer. Lancet 371:1695–1709

    PubMed  CAS  Google Scholar 

  41. Werbrouck J, De Ruyck K, Duprez F, Van Eijkeren M, Rietzschel E, Bekaert S, Vral A, De Neve W, Thierens H (2008) Single-nucleotide polymorphisms in DNA double-strand break repair genes: association with head and neck cancer and interaction with tobacco use and alcohol consumption. Mutat Res 656:74–81

    PubMed  CAS  Google Scholar 

  42. Hoeijmakers JHJ (2001) Genome maintenance mechanisms for preventing cancer. Nature 411:366–374

    PubMed  CAS  Google Scholar 

  43. Scully C, Field JK, Tanzawa H (2000) Genetic aberrations in oral or head and neck squamous cell carcinoma (HNSCC): carcinogen metabolism, DNA repair and cell cycle control. Oral Oncol 36:256–263

    PubMed  CAS  Google Scholar 

  44. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108

    PubMed  Google Scholar 

  45. Chen J, Kyte C, Valcin M, Chan W, Wetmur JG, Selhub J, Hunter DJ MA (2004) Polymorphisms in the one-carbon metabolic pathway, plasma folate levels and colorectal cancer in a prospective study. Int J Cancer 110:617–620

    PubMed  CAS  Google Scholar 

  46. Kruszyna L, Lianeri M, Rydzanicz M, Gajecka M, Szyfter K, Jagodzínski PP (2010) Polymorphic variants of folate metabolism genes and the risk of laryngeal cancer. Mol Biol Rep 37:241–247

    PubMed  CAS  Google Scholar 

  47. Liu H, Jin G, Wang H, Wu W, Liu Y, Qian J (2008) Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case-control study in Chinese population. Lung Cancer 61:21–29

    PubMed  CAS  Google Scholar 

  48. Matakidou A, Galta R, Rudd MF, Webb EL, Bridle H, Eisen T, Houlston RS (2007) Prognostic significance of folate metabolism polymorphisms for lung cancer. Br J Cancer 97:247–252

    PubMed  CAS  Google Scholar 

  49. Li SY, Rong M, Iacopetta B (2006) Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in human breast cancer. Oncol Rep 15:221–225

    PubMed  CAS  Google Scholar 

  50. Barbosa PR, Stabler SP, Trentin R, Carvalho FR, Luchessi AD, Hirata RDC, Hirata MH, Allen RH, Guerra-Shinohara EM (2008) Evaluation of nutritional and genetic determinants of total homocysteine, methylmalonic acid and S-adenosylmethionine/S-adenosylhomocys-teine values in Brazilian childbearing-age women. Clin Chim Acta 388:139–147

    PubMed  CAS  Google Scholar 

  51. Hazra A, Wu K, Kraft P, Fuchs CS, Giovannucci EL (2007) Twenty-four non-synonymous polymorphisms in the one-carbon metabolic pathway and risk of colorectal adenoma in the Nurses’ Health Study. Carcinogenesis 28:1510–1519

    PubMed  CAS  Google Scholar 

  52. Curtin K, Slattery M, Ulrich CM, Bigler J, Levin TR, Wolff RK, Albertsen H, Potter JD, Samowitz WS (2007) Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet. Carcinogenesis 28:1672–1679

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank all those participating in this study and FAMERP/FUNFARME. Research supported by Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP (10/00012-2) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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Authors and Affiliations

  1. Genetics and Molecular Biology Research Unit (UPGEM), Department of Molecular Biology, São José do Rio Preto Medical School (FAMERP), UPGEM-Bloco U6, Avenida Brigadeiro Faria Lima, no. 5416, São José do Rio Preto, SP, 15090-000, Brazil

    Lidia Maria Rebolho Batista da Silva, Ana Lívia Silva Galbiatti, Mariangela Torreglosa Ruiz, Érika Cristina Pavarino & Eny Maria Goloni-Bertollo

  2. Otorhinolaryngology and Head and Neck Surgery Department, São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, SP, Brazil

    Luiz Sérgio Raposo & José Victor Maniglia

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  1. Lidia Maria Rebolho Batista da Silva
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  2. Ana Lívia Silva Galbiatti
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Correspondence to Eny Maria Goloni-Bertollo.

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da Silva, L.M.R.B., Galbiatti, A.L.S., Ruiz, M.T. et al. MTHFD1 G1958A, BHMT G742A, TC2 C776G and TC2 A67G polymorphisms and head and neck squamous cell carcinoma risk. Mol Biol Rep 39, 887–893 (2012). https://doi.org/10.1007/s11033-011-0813-3

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