Log in

Association of TP53 codon 72 and intron 3 16-bp Ins/Del polymorphisms with cervical cancer risk

  • Research Article
  • Published:
Tumor Biology

Abstract

Cervical cancer incidence has grown worldwide, with it being a more significant problem in develo** countries. Invasive squamous cell cervical cancers are preceded by a long phase of preinvasive disease, known as cervical intraepithelial neoplasia. Cervical cancer can develop when the virus takes advantage of any TP53 gene dysfunction of the host organism. TP53 is responsible for encoding the tumor suppressor p53 phosphoprotein, which helps preserve genome integrity. Currently, many studies have focused on genetic polymorphisms as an important contribution to cancer susceptibility, but few related to cervical intraepithelial neoplasia (CIN). Thus, the present study aimed to see whether patients with suspected CIN had TP53 gene polymorphisms that might have contributed to the development of neoplasia. This study included 133 women who were referred to the Cervical Pathology Clinic of the Maternity School Assis Chateaubriand MEAC for suspected cervical lesions. Polymorphism genoty** was carried out by the PCR-RFLP technique using DNA extracted from patients’ blood. The most frequent genotype in both CIN(+) and CIN(−) patients was Arg/Pro TP53 codon 72 and A1A1 for 16-bp Del in intron 3. No risk of cervical cancer was found for the polymorphisms studied. However, a significant association was found when the two polymorphisms were combined: patients with the A1A1/ArgPro genotype were statistically more frequent in the CIN(−) group (p = 0.042), while A2A2-A1A2/ProArg was significantly more frequent in the CIN(+) group. The results of our study suggest that combined analysis of TP53 polymorphisms Arg72Pro and 16-bp Ins/Del may help to monitor the development of CIN in Brazilian women.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Anschau F, Schmitt VM, Gonçalves MAG, Garicochea B. Associação entre o polimorfismo no códon 72 da p53 e as lesões pré-malignas e malignas cervicais. Rev Bras Ginecol Obstet. 2005;27(10):607–12.

    Article  Google Scholar 

  2. Bonafè M, Salvioli S, Barbi C, Mishto M, Trapassi C, Gemelli C, et al. p53 codon 72 genotype affects apoptosis by cytosine arabinoside in blood leukocytes. Biochem Biophys Res Commun. 2002;299(4):539–41.

    Article  PubMed  Google Scholar 

  3. Buitrago-Perez AA, Garaulet G, Vazquez-Carballo A, Paramio JM, Garcia-Escudero R. Molecular signature of HPV-induced carcinogenesis: pRb, p53 and gene expression profiling. Curr Genomics. vol.10. n.1. 2009.

  4. Costa S, Pinto D, Pereira D, Rodrigues H, Cameselle-Teijeiro J, Medieros R, et al. Importance of TP53 codon 72 and intron 3 duplication 16 bp polymorphisms in prediction of susceptibility on breast cancer. BMC Cancer. 2008;8:32.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Freitas TP, Carmo BB, Paula FDF, Rodrigues LF, Fernades AP, Fernandes PA. Molecular detection of HPV 16 and HPV 18 in cervical samples of patients from Belo Horizonte, Minas Gerais, Brazil. Rev Inst Med Trop. 2007;49(5):297–301.

    Article  Google Scholar 

  6. Hu Z, Li X, Qu X, He Y, Ring BZ, Song E, et al. Intron 3 16 bp duplication polymorphism of TP53contributes to cancer susceptibility: a meta-analysis. Carcinogenesis. 2010;31(4):634–47.

    Article  Google Scholar 

  7. IARC - International Agency for Research on Cancer. www.iarc.fr. Acessado em maio/2013.

  8. INCA - Instituto Nacional de Câncer José Alencar Gomes da Silva. Estimativas 2012 – Incidência de Câncer no Brasil. MINISTÉRIO DA SAÚDE. In: http://www.inca.gov.br/estimativa/2012/estimativa20122111.pdf>. Acesso em 15/10/2012.

  9. Jiang P, Liu J, Zeng X, Li W, Tang J. Association of TP53 codon 72 polymorphism with cervical cancer risk in Chinese. Cancer. 2010;197(2):174–8.

    CAS  Google Scholar 

  10. Koshiol J, Hildesheim A, Gonzalez P, Bratti MC, Porras C, Schiffman M, et al. Common genetic variation in TP53 and risk of human papillomavirus persistence and progression to CIN3/cancer revisited. Cancer Epidemiol Biomarkers Prev. 2009;18(5):1631–7. doi:10.1158/1055-9965.EPI-08-0830.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Klug SJ, et al. TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies. Lancet Oncol. v10. 2009.

  12. Malcolm EK, Baber GB, Boyd JC, Stoler MH. Polymorphism at codon 72 of p53 is not associated with cervical cancer risk. n.13 .v. 4. p.373-8. 2000.

  13. Mattick JS. RNA Regulation: a new genetics? Nat Rev Genet. 2004;5:316.

    Article  CAS  PubMed  Google Scholar 

  14. Neves Filho EH, Cordeiro DEF, Vieira APF, Rabenhorst SHB. TP53 codon 72 and intron 3 polymorphisms and mutational status in gastric cancer: an association with tumor onset and prognosis. Pathobiology. 2012.

  15. Piña-Sánchez P, Hernández-Hernández DM, Taja-Chayeb L, Cerda-Flores RM, Gonález-Herrera AL, Rodea-Avila C, et al. Polymorphism in exon 4 of TP53 gene associated to HPV 16 and HPV 18 in Mexican women with cervical cancer. Med Oncol. 2011;28:1507–13.

    Article  PubMed  Google Scholar 

  16. Powell BL, Van Staveren IL, Roosken P, Grieu F, Berns EM, Iacopetta B. Associations between common polymorphisms in TP53 and p21WAF1/Cip1 and phenotypic features of breast cancer. Carcinogenesis. 2002;23:311–5.

    Article  CAS  PubMed  Google Scholar 

  17. Scheurer ME, Tortolero-Luna G, Adler-Storthz. Human papillomavirus infection: biology, epidemiology and prevention. Int J Gynecol Cancer. 2005;15:727–46.

    Article  CAS  PubMed  Google Scholar 

  18. Solomon D, Davey D, Kurman R, Moriarty A, O’connor D, Prey M. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287(16):2114–9.

    Article  PubMed  Google Scholar 

  19. Storey A, Thomas M, Kalita A, Harwood C, Gardiol D, Mantovani F, et al. Role of a p53 polymorphism in the development of human papillomavirus associated cancer. Nature. 1998;393:229–34.

    Article  CAS  PubMed  Google Scholar 

  20. Trifa F, Karray-Chouayekh S, Imed Mabrouk I, Baccouche S, Khabir A, Sellami-Boudawara T, et al. Haplotype analysis of p53 polymorphisms: Arg72Pro, Ins16bp and G13964C in Tunisian patients with familial or sporadic breast cancer. Cancer Epidemiol. 2010;34:184–8.

    Article  CAS  PubMed  Google Scholar 

  21. Gemignani F, Moreno V, Landi S, Moullan N, Chabrier A, Enriquez SG, et al. ATP53polymorphism is associated with increased risk of colorectal cancer and with reduced levels ofTP53mRNA. Oncogene. 2004;23:1954–6.

    Article  CAS  PubMed  Google Scholar 

  22. Sagne C, Marcel V, Amadou A, Hainaut P, Olivier M, Hall J. A meta-analysis of cancer risk associated with the TP53 intron 3 duplication polymorphism (rs17878362): geographic and tumor-specific effects. Cell Death Dis. n.4.e. 492. doi: 10.1038. 2013.

  23. Wu X, Zhao H, Amos CI, Shete S, Makan N, Hong WK, Kadlubar FF, Spitz MR. p53 genotype and haplotypes associated with lung cancer susceptibility and ethnicity. J Natl Cancer Inst. v.19. n.9. 2002.

  24. Agorastos T, Lambropoulos AF, Constantinidis TC, Kotsis A, Bontis JN. p53 codon 72 polymorphism and risk of intra-epithelial and invasive cervical neoplasia in Greek women. Eur J Cancer Prev. p.113-8. 2000.

  25. Tornesello ML, Buonaguro L, Buonaguro FM. Mutations of the TP53 gene in adenocarcinoma and squamous cell carcinoma of the cervix: a systematic review. Gynecol Oncol. 2012.

  26. Fernandes TA, Lima GL, DE Sousa FC, Fernandes JV, Meissner RV. Evaluation of the polymorphisms in the exons 2 to 4 of the TP53 in cervical carcinoma patients from a Brazilian population. Cell Mol Biol. 2008.

  27. Marcel V, Tran PLT, Sagne C, Martel-Planche G, Vaslin L, Meulade-Fichou MP, Hall J, Mergny JL, Hainaut P, Dyck EV. G-quadruplex structures in TP53 intron 3: role in alternative splicing and in production of p53 mRNA isoforms. Oxford Journal. 2010.

  28. Mitra S, Misra C, Singh RK, Panda CK, Roychoudhury S. Association of specific genotype and haplotype of p53 gene with cervical cancer in India. J Clin Pathol. 2005.

  29. Chan PKS, Li WH, Chan MYM, Ma WL, Cheung JLK, Cheng AF. High prevalence of human papillomavirus type 58 in Chinese women with cervical cancer and precancerous lesions. J Med Virol. 1999.

  30. Munõz N. Human papillomavirus and cancer: the epidemiological evidence. J Clin Virol. 2000.

  31. Osorio A, Martinez-Delgado B, Pollan M, Cuadros M, Urioste M, Tor-Renteras C, Melchor L, Diez O, DE La HM, Velasco E, Gonzalez-Sarmiento R, Caldes T, Alonso C, Benitez J. A haplotype containing the p53 polymorphisms Ins16bp and Arg72Pro modifies cancer risk in BRCA2 mutation carriers. Hum Mutat. 2006.

  32. Singhal P, Hussain S, Thakur N, Batra S, Salhan S, Bhambani S, Bharadwaj M. Association of MDM2 and p53 polymorphisms with the advancement of cervical carcinoma. DNA and Cell Biology. V. 32, Nº. 1, ªMary Ann Liebert, Inc. Pp. 19–27. DOI: 10.1089/dna.2012.1718. 2013.

  33. Zhou, X, Gu Y, Zhang SL. Association between p53 codon 72 polymorphism and cervical cancer risk among Asians: a Huge Review and Meta-analysis. Asian Pacific J Cancer Prev, 13 (10), 4909-4914. DOI:10.7314/APJCP.2012.13. 10.4909. 2012.

Download references

Acknowledgments

We thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 402694/2008-2 for financial support. Dr. A. Leyva (USA) helped with English editing of the manuscript.

Conflicts of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Silvia Helena Barem Rabenhorst.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Laprano, T.D.R., Lemos, É.H., Cunha, L.M.P. et al. Association of TP53 codon 72 and intron 3 16-bp Ins/Del polymorphisms with cervical cancer risk. Tumor Biol. 35, 7435–7440 (2014). https://doi.org/10.1007/s13277-014-1988-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-1988-8

Keywords

Navigation