Skip to main content

Advertisement

SpringerLink
Log in

Tyms double (2R) and triple repeat (3R) confers risk for human oral squamous cell carcinoma

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

The oral cancer is responsible for approximately 3 % of cases of cancer in Brazil. Epidemiological studies have associated low folate intake with an increased risk of epithelial cancers, including oral cancer. Folic acid has a key role in DNA synthesis, repair, methylation and this is the basis of explanations for a putative role for folic acid in cancer prevention. The role of folic acid in carcinogenesis may be modulated by polymorphism C677T in MTHFR and tandem repeats 2R/3R in the promoter site of TYMS gene that are related to decreased enzymatic activity and quantity and availability of the enzyme, respectively. These events cause a decrease in the synthesis, repair and DNA methylation, which can lead to a disruption in the expression of tumor suppressor genes as TP53. The objective of this study was investigate the distribution of polymorphisms C677T and tandem repeats 2R/3R associated with the development of oral squamous cell carcinoma (OSCC). 53 paraffin-embedded samples from patients who underwent surgery but are no longer at the institution and 43 samples collected by method of oral exfoliation by cytobrush were selected. 132 healthy subjects were selected by specialists at the dental clinics of the Faculdade de Odontologia de Pernambuco—FOP. The MTHFR genotyping was performed by PCR–RFLP, and the TYMS genotyping was performed by conventional PCR. Fisher’s Exact test at significant level of 5 %. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used to measure the strength of association between genotype frequency and OSCC development. The results were statistically significant for the tandem repeats of the TYMS gene (p = 0.015). The TYMS 2R3R genotype was significantly associated with the development of OSCC (OR = 3.582; 95 % CI  1.240–10.348; p = 0.0262) and also the genotype 3R3R (OR = 3.553; 95 % CI  1.293–9.760; p = 0.0345). When analyzed together, the TYMS 2R3R + 3R3R genotypes also showed association (OR = 3.518; 95 % CI  11.188–10.348; p = 0.0177). No differences for the MTHFR C677T polymorphisms distribution were found between the oral cancer patients and controls subjects in our study (p = 0.499). Therefore, these data suggest that determination of TYMS tandem repeats could provide information on the comprehension of the risk factors and prevention of the OSCC.

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. Ferlay j et al (2004) Cancer incidence, mortality and prevalence worldwide. Cancer Base 5(2):291–306

    Google Scholar 

  2. Instituto Nacional de Câncer (INCA/MS) (2011) Estimativa da incidência e mortalidade por câncer no Brasil http://www.inca.gov.br. Accessed Nov 2011

  3. Carvalho C (2003) Cresce incidência de câncer de boca no Brasil. Rev Bras Odontol 60:36–39

    Google Scholar 

  4. Antunes A, Silva PV, Avelar RL, Santos TS (2007) Câncer da língua: estudo retrospectivo de vinte anos. Rev Bras Cir Cabeça Pescoço 36(3):152–154

    Google Scholar 

  5. Hashibe M, Boffetta P, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Mates D, Fabiánová E, Rudnai P, Brennan P (2007) Contribution of tobacco and alcohol to the high rates of squamous cell carcinoma of the supraglottis and glottis in Central Europe. Am J Epidemiol 165(7):814–820

    Article  PubMed  Google Scholar 

  6. Altieri A, Garavello W, Bosetti C, Gallus S, La Vecchia C (2005) Alcohol consumption and risk of laryngeal cancer. Oral Oncol 41(10):956–965

    Article  CAS  PubMed  Google Scholar 

  7. Tran N, Rose BR, O’Brien CJ (2007) Role of human papillomavirus in the etiology of head and neck cancer. Head Neck 29(1):64–70

    Article  PubMed  Google Scholar 

  8. Boccia S, Cadoni G, Sayed-Tabatabaei FA, Volante M, Arzani D, De Lauretis A, Cattel C, Almadori G, van Duijn CM, Paludetti G, Ricciardi G (2008) CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms, smoking, consumption of alcohol and fruit and vegetables and risk of head and neck cancer. J Cancer Res Clin Oncol 134(1):93–100

    Article  CAS  PubMed  Google Scholar 

  9. Sturgis E, Wei Q (2002) Genetic susceptibility—molecular epidemiology of head and neck cancer. Curr Opin Oncol 14:310–317

    Article  PubMed  Google Scholar 

  10. Powers HJ (2005) Interaction among folate, riboflavin, genotype, and cancer, with reference to colorectal and cervical cancer. J Nut 135(12):2960S–2966S

    CAS  Google Scholar 

  11. Solomon PR, Selvam GS, Shanmugam G (2008) Polymorphism in ADH and MTHFR genes in oral Squamous cell carcinoma of Indians. Oral Dis 14:633–639

    Article  CAS  PubMed  Google Scholar 

  12. Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. PNAS 96:12810–12815

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Niclot S, Pruvot Q, Besson C (2006) Implication of the folate–methionine metabolism pathways in susceptibility to follicular lymphomas. Blood 108:278–285

    Article  CAS  PubMed  Google Scholar 

  14. Bailey LB, Gregory JF III (1999) Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr 129:919–922

    CAS  PubMed  Google Scholar 

  15. Ulvik A, Vollset SE, Hansen S (2004) Colorectal cancer and the methylenetetrahydrofolate reductase 677C→T and methionine synthase 2756A→G polymorphisms: a study of 2,168 case–control pairs from the JANUS cohort. Cancer Epidemiol Biomark Prev 13:2175–2180

    CAS  Google Scholar 

  16. Lima ELS, Silva VC, Silva HDA, Bezerra AM, Morais VLL, Morais AL, Cruz RV, Barros MHM, Hassan R, Freitas AC, Muniz MTC (2010) MTR polymorphic variant A2756G and retinoblastoma risk in Brazilian children. Pediatr Blood Cancer 54:904–908

    PubMed  Google Scholar 

  17. Stern LL, Mason JB, Selhub J (2000) Genomic DNA hypomethylation: a characteristic of most cancers is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the MTHFR gene. Cancer Epidemiol Biomark Prev 9:849–853

    CAS  Google Scholar 

  18. Frosst P, Blom HJ, Milos R (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. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998) A second genetic polymorphism in methylene tetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64:169–172

    Article  CAS  PubMed  Google Scholar 

  20. Li G et al (2005) Genetic polymorphisms of p21 are associated with risk of squamous cell carcinoma of the head and neck. Carcinogenesis 26:1596–1602

    Article  CAS  PubMed  Google Scholar 

  21. Wang XQ et al (2001) A possible role of p73 on the modulation of p53 level through MDM2. Cancer Res 61:1598–1603

    CAS  PubMed  Google Scholar 

  22. Sailasree R, Nalinakumari KR, Sebastian P, Kannan S (2011) Influence of methylenetetrahydrofolate reductase polymorphisms in oral cancer patients. J Oral Pathol Med 40:61–66

    Article  CAS  PubMed  Google Scholar 

  23. Kaneda S, Takeishi K, Ayusawa D (1987) Role in translation of a triple tandemly repeated sequence in the 5′-untranslated region of human thymidylate synthase mRNA. Nucleic Acids Res 15:1259–1270

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Zhang Z, Shi Q, Sturgis EM, Spitz MR, Hong WK, Wei Q (2004) Thymidilate synthase 5′- and 3′-untranslated region polymorphisms associated with risk and progression of squamous cell carcinoma of the head and neck. Clin Cancer Res 10:7903–7910

    Article  CAS  PubMed  Google Scholar 

  25. Galbarthe, Shimoda T, Haainaut P, Nakamura Y, Field JK, Inove H (2000) Squamous cell carcinoma of the esophagus. In: Hamilton, SR, Aaltone, LA, World Health Organization Classification of Tumors (eds) Pathology and genetics of tumors of the digest system. IARC Press, Lyon pp 9–11

  26. MacDonald DG (2000) Tumors of the oral cavity. In: Fletcher CD (ed) Diagnostic histopathology of tumors. Churchill LivingStone, London, pp 209–230

    Google Scholar 

  27. Nascimento EM, Spinelli MO, Rodrigues CJ, Bozzini N (2003) Protocol of the DNA extraction from paraffin material in order to analyze microsatellites in uterine leiomyoma. Genet Mol Biol 26:27

    Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, Den Heijer M, Kluutmans LA, Van den heuvel LP, Rozen R (1995) A candidate genetic risk factor for vascular disease: a common mutation at the methylenetetrahydrofolate reductase locus. Nat Gen 10:110–113

    Article  Google Scholar 

  30. Skibola CF, Marlyn ST, Hubbard A, Shane A, Roberts AC, Law GR, Rollinson S, Roman E, Cartwright RA, Morgan G (2002) Polymorphism in the thymidilato synthase and serine hydroximethyiltransferase genes and risk of adult acute lymphocytic leukemia. Blood 99:3786–3791

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Pogribny IP, Muskhelishvili L, Miller BJ (1997) Presence and consequence of uracil in preneoplastic DNA from folate/methyl-deficient rats. Carcinogenesis 18:2071–2076

    Article  CAS  PubMed  Google Scholar 

  33. Heijmans BT, Boer JM, Suchiman HE (2003) A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer. Cancer Res 63:1249–1253

    CAS  PubMed  Google Scholar 

  34. Aune D, Deneo-Pellegriniz H, Ronco AL, Boffetta P, Acosta G, Mendilaharsu M, De Stefani E (2010) Dietary folate intake and the risk of 11 types of cancer: a case–control study in Uruguay. Ann Oncol 22(2):444–451

    Article  PubMed  Google Scholar 

  35. Zing JM, Jones PA (1997) Genetic and epigenetic aspects of DNA methylation on genome expression, evolution, mutation and carcinogenesis. Carcinogenesis 18:869–882

    Article  Google Scholar 

  36. Duthie SJ (1999) Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull 55:578–592

    Article  CAS  PubMed  Google Scholar 

  37. Mokarram P, Naghibalhossaini F, Firoozi MS (2008) Methylenetetrahydrofolate reductase C677T genotype affects promoter methylation of tumor-specific genes in sporadic colorectal cancer through an interaction with folate/vitamin B12 status. World J Gastroenterol 14:3662–3671

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. 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 

  39. Ulrich CM, Curtin K, Potter JD (2005) Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer. Cancer Epidemiol Biomark Prev 14:2509–2516

    Article  CAS  Google Scholar 

  40. Guerreiro CS, Carmona B, Gonçalves S (2008) Risk of colorectal cancer associated with the C677T polymorphism in 5,10-methylenetetrahydrofolate reductase in Portuguese patients depends on the intake of methyl-donor nutrients. Am J Clin Nutr 88:1413–1418

    CAS  PubMed  Google Scholar 

  41. Götze T, Röcken C, Röhl FW (2007) Gene polymorphisms of folate metabolizing enzymes and the risk of gastric cancer. Cancer Lett 251:228–236

    Article  PubMed  Google Scholar 

  42. Yuan JM, Lu SC, Van Den Berg D (2007) Genetic polymorphisms in the methylenetetrahydrofolate reductase and thymidylate synthase genes and risk of hepatocellular carcinoma. Hepatology 46:749–758

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Skibola CF, Forrest MS, Coppede F (2005) Polymorphisms and haplotypes in folate metabolizing genes and risk of non-Hodgkin’s lymphoma. Blood 105:2155–2162

    Google Scholar 

  44. Hishida A, Matsuo H, Hamajima N, Ito H, Ogura M, Kagami Y, Taji H, Morishima Y, Emi N, Tajima K (2003) Associations between polymorphisms in the thymidilate synthase and serine hydroxymethyltransferase genes and susceptybility to malignant lymphoma. Haematologica 88:159–166

    CAS  PubMed  Google Scholar 

  45. Krajinovic M, Costa SC (2002) Polymorphism of the thymidylate syntase gene and outcome of acute lymphoblastic leukemia. Lancet 359:1033–1034

    Article  CAS  PubMed  Google Scholar 

  46. Goodle EL, Potter JD, Bigler J, Ulrich CM (2004) Methionine syntase D919G polymorphism, and colorectal adenoma risk. Cancer Epidemol Biomark 13:157–162

    Article  Google Scholar 

  47. Zhang Z, Xu Y, Zhou J, Wang X, Wang L, Hu X, Guo J, Wei Q, Shen H (2005) Polymorphisms of thymidylate synthase in the 5′-and 3′-untranslated regions associated with risk of gastric cancer in South China: a case–control analysis. Carcinogenesis 26(10):1764–1769

    Article  CAS  PubMed  Google Scholar 

  48. Xu W, Long JR, Zheng W, Ruan ZX, Cai Q, Cheng JR, Zhao GM, Xiang YB, Shu XO (2009) Association of thymidylate synthase gene with endometrial cancer risk in a Chinese population. Cancer Epidemiol Biomark Prev 18(2):579–584

    Article  CAS  Google Scholar 

  49. Trinh BN, Ong CN, Coetzee GA, Yu MC, Laird PW (2002) Thymidylate synthase: a novel genetic determinant of plasma homocysteine and folate levels. Hum Genet 111:299–302

    Article  CAS  PubMed  Google Scholar 

  50. Hori T, Ayusawa D, Shimizu K, Koyama H, Seno T (1984) Chromosome breakage induced by thymidylate stress in thymidylate synthase-negative mutants of mouse FM3A cells. Cancer Res 44:703–709

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the patients and their families, whose collaboration and understanding have made this work possible. This study was supported by FACEPE (Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível superior). We thank Hospital de Câncer de Pernambuco, for providing the sample of patients and the support provide during this study.

Conflict of Interest

The authors report no declarations of interest.

Author information

Authors and Affiliations

  1. Laboratório de Biologia Molecular, Centro de Oncohematologia Pediátrica (CEONHPE), Hospital Universitário Oswaldo Cruz–HUOC/PE, Universidade de Pernambuco—UPE, Recife, Brazil

    Alexandre Medeiros Bezerra, Thalita Araújo Sant’Ana, Adriana Vieira Gomes & Maria Tereza Cartaxo Muniz

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

    Alexandre Medeiros Bezerra, Thalita Araújo Sant’Ana, Aurora Karla de Lacerda Vidal & Maria Tereza Cartaxo Muniz

  3. Faculdade de Ciências Médicas (FCM), Universidade de Pernambuco—UPE, Recife, Brazil

    Adriana Vieira Gomes

Authors
  1. Alexandre Medeiros Bezerra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thalita Araújo Sant’Ana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adriana Vieira Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aurora Karla de Lacerda Vidal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Tereza Cartaxo Muniz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Tereza Cartaxo Muniz.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bezerra, A.M., Sant’Ana, T.A., Gomes, A.V. et al. Tyms double (2R) and triple repeat (3R) confers risk for human oral squamous cell carcinoma. Mol Biol Rep 41, 7737–7742 (2014). https://doi.org/10.1007/s11033-014-3494-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-014-3494-x

Keywords

Search

Navigation