Document Type : Original Article

Authors

1 Assistant Professor of Cellular & Molecular Biology, Department of Biology, Faculty of Science, Azarbaijan Shahid Madani University, Tabriz, Iran

2 Ph.D. candidate of Medical Genetics, Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

3 Professor of Radiobiology, Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran

4 M.Sc. of Molecular Genetics, Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran

Abstract

Background:Many case-control investigations have showed the correlation of TP53 gene polymorphisms with the risk of breast cancer. However, the findings are not consistent. It has been suggested that the investigation of P53 genotype combinations and haplotypes may be more helpful than the detection of single polymorphisms. In the present study, we investigated the association of P53 intron 3 and codon 72 polymorphisms, as well as their Haplotypes and genotype combinations, with the development of breast cancer among Azeri women of Iran.
Methods:A total of 143 Iranian-Azeri females suffering from breast cancer and 160 ethnically and age-matched healthy females participated in this study. Intron 3 genotype was indicated by length analysis of PCR amplicon on polyacrylamide gels and allele specific–polymerase chain reaction (AS-PCR) was applied for genotyping Arg72Pro variation. Data analysis was performed using the JavaStat online statistics package and SHEsis online program.
Results: Our findings did not show a significant association of P53 intron 3 and codon 72 polymorphisms with the risk of breast neoplastic tumors among Iranian-Azeri women. However, the (-16ins/+16ins) (Arg/Arg) combined genotype and (+16Ins-Arg) haplotype had a higher frequency in patients in comparison with the control group (OR=3.816;  95%CI: 0.906-18.459;  p =0.047 and OR=3.941;  95%CI: 1.583-9.812;  p =0.002, respectively).
Conclusion:In our study, (-16ins/+16ins) (Arg/Arg) genotype combination and (+16ins-Arg) haplotype showed significant correlation with the increased susceptibility to breast cancer development in Iranian-Azeri females.

Keywords

  1. Enayatrad M, Amoori N, Salehiniya H. Epidemiology and trends in breast cancer mortality in Iran. Iran J Public Health 2015; 44(3):430-1.
  2. Ma CX, Ellis MJ. The Cancer Genome Atlas: clinical applications for breast cancer. Oncology (Williston Park) 2013; 27(12):1263-9.
  3. Dumay A, Feugeas JP, Wittmer E, Lehmann-Che J, Bertheau P, Espie M, et al. Distinct tumor protein p53 mutants in breast cancer subgroups. Int J Cancer 2013; 132(5):1227-31.
  4. Merino D, Malkin D. P53 and hereditary cancer. Subcell Biochem 2014; 85:1-16.
  5. Walerych D, Napoli M, Collavin L, Del Sal G. The rebel angel: mutant p53 as the driving oncogene in breast cancer. Carcinogenesis 2012; 33(11):2007-17.
  6. Bonafe M, Ceccarelli C, Farabegoli F, Santini D, Taffurelli M, Barbi C, et al. Retention of the p53 codon 72 arginine allele is associated with a reduction of disease-free and overall survival in arginine/proline heterozygous breast cancer patients. Clin Cancer Res 2003; 9(13):4860-4.
  7. Dumont P, Leu JI, Della Pietra AC, 3rd, George DL, Murphy M. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 2003; 33(3):357-65.
  8. Ozeki C, Sawai Y, Shibata T, Kohno T, Okamoto K, Yokota J, et al. Cancer susceptibility polymorphism of p53 at codon 72 affects phosphorylation and degradation of p53 protein. J Biol Chem 2011; 286(20):18251-60.
  9. Khan MH, Khalil A, Rashid H. Evaluation of the p53 Arg72Pro polymorphism and its association with cancer risk: a HuGE review and meta-analysis. Genet Res (Camb) 2015; 97:e7.
  10. Wu X, Zhao H, Amos CI, Shete S, Makan N, Hong WK, et al. p53 genotypes and haplotypes associated with lung cancer susceptibility and ethnicity. J Natl Cancer Inst 2002; 94(9):681-90.
  11. Marcel V, Tran PL, Sagne C, Martel-Planche G, Vaslin L, Teulade-Fichou MP, et al. G-quadruplex structures in TP53 intron 3: role in alternative splicing and in production of p53 mRNA isoforms. Carcinogenesis 2011; 32(3):271-8.
  12. Morten BC, Wong-Brown MW, Scott RJ, Avery-Kiejda KA. The presence of the intron 3 16 bp duplication polymorphism of p53 (rs17878362) in breast cancer is associated with a low Delta40p53:p53 ratio and better outcome. Carcinogenesis 2016; 37(1):81-6.
  13. Gemignani F, Moreno V, Landi S, Moullan N, Chabrier A, Gutierrez-Enriquez S, et al. A TP53 polymorphism is associated with increased risk of colorectal cancer and with reduced levels of TP53 mRNA. Oncogene 2004; 23(10):1954-6.
  14. Woelfelschneider A, Popanda O, Lilla C, Linseisen J, Mayer C, Celebi O, et al. A distinct ERCC1 haplotype is associated with mRNA expression levels in prostate cancer patients. Carcinogenesis 2008; 29(9):1758-64.
  15. Hu Z, Li X, Qu X, He Y, Ring BZ, Song E, et al. Intron 3 16 bp duplication polymorphism of TP53 contributes to cancer susceptibility: a meta-analysis. Carcinogenesis 2010; 31(4):643-7.
  16. Eskandari-Nasab E, Hashemi M, Amininia S, Ebrahimi M, Rezaei M, Hashemi SM. Effect of TP53 16-bp and beta-TrCP 9-bp INS/DEL polymorphisms in relation to risk of breast cancer. Gene 2015; 568(2):181-5.
  17. 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 2013; 4:e492.
  18. Gudkov AV, Komarova EA. p53 and the Carcinogenicity of Chronic Inflammation. Cold Spring Harb Perspect Med 2016; 6(11).
  19. Wu D, Zhang Z, Chu H, Xu M, Xue Y, Zhu H, et al. Intron 3 Sixteen Base Pairs Duplication Polymorphism of P53 Contributes to Breast Cancer Susceptibility: Evidence from Meta-Analysis. PLoS ONE 2013; 8(4): e61662.
  20. He XF, Su J, Zhang Y, Huang X, Liu Y, Ding DP, et al. Association between the p53 polymorphisms and breast cancer risk: meta-analysis based on case-control study. Breast Cancer Res Treat 2011; 130(2):517-29.
  21. Dehghan R, Hosseinpour Feizi MA, Pouladi N, Babaei E, Montazeri V, Fakhrjoo A, et al. Association of p53 (−16ins-pro) haplotype with the decreased risk of differentiated thyroid carcinoma in Iranian-Azeri patients. Pathology & Oncology Research 2015; 21(2):449-54.
  22. Zhang Z, Wang M, Wu D, Wang M, Tong N, Tian Y, et al. P53 codon 72 polymorphism contributes to breast cancer risk: a meta-analysis based on 39 case-control studies. Breast Cancer Res Treat 2010; 120(2):509-17.
  23. Hou J, Jiang Y, Tang W, Jia S. P53 codon 72 polymorphism and breast cancer risk: A meta-analysis. Exp Ther Med 2013; 5(5):1397-1402.
  24. Trifa F, Karray-Chouayekh S, 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(2):184-8.
  25. Buyru N, Altinisik J, Demokan S, Dalay N. p53 genotypes and haplotypes associated with risk of breast cancer. Cancer Detect Prev 2007; 31(3):207-13.
  26. Sjalander A, Birgander R, Hallmans G, Cajander S, Lenner P, Athlin L, et al. p53 polymorphisms and haplotypes in breast cancer. Carcinogenesis 1996; 17(6):1313-6.