Molecular Epidemiology of Breast Cancer among Iranian-Azeri Population based on P53 Research

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

3 Associate Professor of Molecular Biology & Biochemistry, Department of Cellular and Molecular Biology, School of Biology, College of Sciences, University of Tehran, Tehran, Iran

4 Ph.D. candidate of Molecular Genetics, Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran

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

Abstract

Background: This study was done in order to enhance our understanding about molecular and epidemiological features of breast cancer among the Azeri population with special emphasis on the detection of TP53 mutations. We also analyzed the role of the P53codon72 polymorphism (rs1042522) and its role in susceptibility to breast cancer.
Methods: Tumor and control samples were collected from 248 patients and 189 controls. TP53 mutations in exons4-9 and adjacent intronic regions were detected by direct sequencing in 130 of these tumor samples. Allele-specific PCR amplification (ARMS-PCR) was used to detect polymorphisms at P53codon72 in 248 patients and 189 controls. Data were analyzed using χ2 test or Fisher's exact and a p value of <0.05 was considered significant.
Results: We identified alterations in 17.69% of the exonic and intronic regions within the TP53. We detected 23 mutant and 107 non-mutant samples. These mutations comprised 21 single-base substitutions (15-transitions and 6-transversions), one deletion and one complex. Exon6 was identified as a highly mutable region, with ten out of all 23 (43.47%) observed mutations. We did not observe a significant association between polymorphism and mutation status (p>0.05). Also, the results did not show a significant correlation between P53 mutational status and clinicopathological features. Distribution differences in the P53codon72 polymorphism between the cases and controls were not statistically significant (p>0.05).
Conclusion: It might be concluded that P53 mutational status and codon72 polymorphism could not be considered as biomarker for breast cancer risk and its clinical features in the studied population. However, further investigations are needed to support these findings.

Keywords


  1. American Cancer Society. Breast Cancer Facts & Figures 2013-2014. Atlanta: American cancer society, Inc 2013. Available from: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2013-2014.pdf
  2. Pathy NB, Yip CH, Taib NA, Hartman M, Saxena N, Iau P, et al. Breast cancer in a multi-ethnic Asian setting: results from the Singapore-Malaysia hospital-based breast cancer registry. Breast 2011; 20 Suppl 2:S75-80.
  3. Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, Murray CJ, et al. Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet 2011; 378(9801):1461-84.
  4. Pouladi N, Kouhsari SM, Feizi MH, Dehghan R, Azarfam P, Farajzadeh D. Lack of association of intron 3 16 bp polymorphism of TP53 with breast cancer among Iranian-Azeri patients. Asian Pac J Cancer Prev 2014; 15(6):2631-4.
  5.  Xu Y, Deng Q, He B, Pan Y, Li R, Gao T, et al. The diplotype Fas -1377A/-670G as a genetic marker to predict a lower risk of breast cancer in Chinese women. Tumor Biol2014; 35(9):9147-61.
  6. Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer 2009; 9(10):749-58.
  7. Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell 2009; 137(3):413-31.
  8. Hosking CR. Celebrating 30 years of p53 research. Trends in Cell Biology 2010; 20(1):1.
  9. Pouladi N, Kouhsari SM, Feizi MH, Gavgani RR, Azarfam P. Overlapping region of p53/wrap53 transcripts: mutational analysis and sequence similarity with microRNA-4732-5p. Asian Pac J Cancer Prev 2013; 14(6):3503-7.
  10. Aylon Y, Oren M. The Paradox of p53: What, How, and Why? Cold Spring Harb Perspect Med 2016; 6(10). pii: a026328.
  11. Whibley C, Pharoah PD, Hollstein M. p53 polymorphisms: cancer implications. Nat Rev Cancer 2009; 9(2):95-107.
  12. Bartlett JMS. Ovarian Cancer Methods and Protocols. New Jersey: Springer; 2000. p. 262–300.
  13. 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(6682):229-34.
  14. Khani H, Hosseinpourefeizi M, Pouladi N, Chaparzadeh N, Montazeri V, Azarfam P. Detection of p53 gene exons 5 and 6 mutations among east Azerbaijani women with breast Cancer. Journal of Zanjan University of Medical Sciences 2012; 20(78):36-46. In Persian
  15. Pouladi N, Hosseinpour Feizi M, Khani H. Evaluation of mutations in exons 7 and 8 of TP53 gene in breast cancer patients from Azarbaijan. Journal of Babol University of Medical Sciences 2016; 18(2):19-25. In Persian
  16. Takahashi T, D'Amico D, Chiba I, Buchhagen DL, Minna JD. Identification of intronic point mutations as an alternative mechanism for p53 inactivation in lung cancer. J Clin Invest 1990; 86(1):363-9.
  17. Bhoo-Pathy N, Yip CH, Hartman M, Uiterwaal CS, Devi BC, Peeters PH, et al. Breast cancer research in Asia: adopt or adapt Western knowledge? Eur J Cancer 2013; 49(3):703-9.
  18. Leong SP, Shen ZZ, Liu TJ, Agarwal G, Tajima T, Paik NS, et al. Is breast cancer the same disease in Asian and Western countries? World J Surg 2010; 34(10):2308-24.
  19. Agarwal G, Pradeep PV, Aggarwal V, Yip CH, Cheung PS. Spectrum of breast cancer in Asian women. World J Surg 2007; 31(5):1031-40.
  20. Coleman MP, Quaresma M, Berrino F, Lutz JM, De Angelis R, Capocaccia R, et al. Cancer survival in five continents: a worldwide population-based study (CONCORD). Lancet Oncol 2008; 9(8):730-56.
  21. Hjortsberg L, Rubio-Nevado JM, Hamroun D, Claustres M, Béroud C, Soussi T. The p53 Mutation handbook 2.0, available online; http://p53.free.fr. 2008
  22. Eachkoti R, Hussain I, Afroze D, Aejazaziz S, Jan M, Shah ZA, et al. BRCA1 and TP53 mutation spectrum of breast carcinoma in an ethnic population of Kashmir, an emerging high-risk area. Cancer Lett 2007; 248(2):308-20.
  23. Feki A, Irminger-Finger I. Mutational spectrum of p53 mutations in primary breast and ovarian tumors. Crit Rev Oncol Hematol 2004; 52(2):103-16.
  24. Silwal-Pandit L, Vollan HK, Chin SF, Rueda OM, McKinney S, Osako T, et al. TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res 2014; 20(13):3569-80.
  25. Arcand SL, Akbari MR, Mes-Masson AM, Provencher D, Foulkes WD, Narod SA, et al. Germline TP53 mutational spectrum in French Canadians with breast cancer. BMC Med Genet 2015; 16:24.
  26. Olivier M, Petitjean A, Marcel V, Petre A, Mounawar M, Plymoth A, et al. Recent advances in p53 research: an interdisciplinary perspective. Cancer Gene Ther 2009; 16(1):1-12.
  27. Lane D. p53: out of Africa. Genes Dev 2016; 30(8):876-7.
  28. Kung CP, Leu JI, Basu S, Khaku S, Anokye-Danso F, Liu Q, et al. The P72R polymorphism of p53 predisposes to obesity and metabolic dysfunction. Cell Rep 2016; 14(10):2413-25.
  29. Noma C, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S. Association of p53 genetic polymorphism (Arg72Pro) with estrogen receptor positive breast cancer risk in Japanese women. Cancer Lett 2004; 210(2):197-203.
  30. Hu Y, McDermott MP, Ahrendt SA. The p53 codon 72 proline allele is associated with p53 gene mutations in non-small cell lung cancer. Clin Cancer Resm 2005; 11(7):2502-9.
  31. DeVita VT, Chu E. A history of cancer chemotherapy. Cancer Res 2008; 68(21):8643-53.
  32. Cortes-Funes H, Coronado C. Role of anthracyclines in the era of targeted therapy. Cardiovasc Toxicol 2007; 7(2):56-60.
  33. Cheok CF, Lane DP. New developments in small molecules targeting p53 pathways in anticancer therapy. Drug Dev Res 2008; 69: 289–296.
  34. Burmakin M, Shi Y, Hedstrom E, Kogner P, Selivanova G. Dual targeting of wild-type and mutant p53 by small molecule RITA results in the inhibition of N-Myc and key survival oncogenes and kills neuroblastoma cells in vivo and in vitro. Clin Cancer Res 2013; 19(18):5092-103.
  35. Farnebo M, Bykov VJ, Wiman KG. The p53 tumor suppressor: a master regulator of diverse cellular processes and therapeutic target in cancer. Biochem Biophys Res Commun 2010; 396(1):85-9.
  36. Boeckler FM, Joerger AC, Jaggi G, Rutherford TJ, Veprintsev DB, Fersht AR. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci U S A 2008; 105(30):10360-5.
  37. Joerger AC, Ang HC, Fersht AR. Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proc Natl Acad Sci U S A 2006; 103(41):15056-61.
  38. Essmann F, Schulze-Osthoff K. Translational approaches targeting the p53 pathway for anti-cancer therapy. Br J Pharmacol 2012; 165(2):328-44.
  39. Diamandis M, White NM, Yousef GM. Personalized medicine: marking a new epoch in cancer patient management. Mol Cancer Res 2010; 8(9):1175-87.
  40. Collins F. Has the revolution arrived? Nature 2010; 464(7289):674-5.
  41. Cheok CF, Lane DP. New developments in small molecules targeting p53 pathways in anticancer therapy. Drug Dev Res 2008; 69: 289–296.
  42. Burmakin M, Shi Y, Hedstrom E, Kogner P, Selivanova G. Dual targeting of wild-type and mutant p53 by small molecule RITA results in the inhibition of N-Myc and key survival oncogenes and kills neuroblastoma cells in vivo and in vitro. Clin Cancer Res 2013; 19(18):5092-103.
  43. Farnebo M, Bykov VJ, Wiman KG. The p53 tumor suppressor: a master regulator of diverse cellular processes and therapeutic target in cancer. Biochem Biophys Res Commun 2010; 396(1):85-9
  44. Boeckler FM, Joerger AC, Jaggi G, Rutherford TJ, Veprintsev DB, Fersht AR. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci U S A 2008; 105(30):10360-5.
  45. Joerger AC, Ang HC, Fersht AR. Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proc Natl Acad Sci U S A 2006; 103(41):15056-61.
  46. Essmann F, Schulze-Osthoff K. Translational approaches targeting the p53 pathway for anti-cancer therapy. Br J Pharmacol 2012; 165(2):328-44.
  47. Diamandis M, White NM, Yousef GM. Personalized medicine: marking a new epoch in cancer patient management. Mol Cancer Res 2010; 8(9):1175-87.
  48. Collins F. Has the revolution arrived? Nature 2010; 464(7289):674-5.