Tumor Biology

, Volume 35, Issue 12, pp 12403–12408 | Cite as

Association of TP53 PIN3 polymorphism with breast cancer in Moroccan population

  • Chaymaa Marouf
  • Amal Tazzite
  • Brehima Diakité
  • Hassan Jouhadi
  • Abdellatif Benider
  • Sellama Nadifi
Research Article


TP53 is a tumor suppressor gene involved in cell cycle progression control, DNA damage repair, genomic stability, and apoptosis. Some polymorphisms in this gene have been associated with the development of a number of cancers including breast carcinoma. PIN3 Ins16bp polymorphism has been widely studied in different populations for an association with breast cancer risk. In most case-control studies, a duplicated allele has been more frequent in cases rather than controls but there are also inconsistent results. The present study aimed to assess the association of PIN3 Ins16bp polymorphism of p53 with breast cancer risk in Moroccan population. This case-control study was performed on 105 female patients with confirmed breast cancer and 114 healthy controls. The genotype frequency was 69.5 % (A1A1), 26.7 % (A1A2), and 3.8 % (A2A2) in patients and 68.4 % (A1A1), 24.6 % (A1A2), and 7 % (A2A2) in controls. No statistically significant association was observed between PIN3 Ins16bp polymorphism and breast cancer risk with odds ratio of 1.07 (confidence interval (CI) = 0.58–1.97, p = 0.83) for the heterozygous A1A2 and 0.53 (CI = 0.15–1.85, p = 0.32) for mutated homozygous A2A2.According to our preliminary genetic analysis, PIN3 Ins16pb polymorphism could not be assessed as a marker of risk factor for predisposition to breast cancer in Moroccan population. However, a high frequency of A2 allele (19.3 %) in our population suggested that PIN3 Ins16pb polymorphism may be a valuable marker for study in other cancers with larger groups.


TP53 PIN3 Ins16bp polymorphism Breast carcinoma Morocco 



We would like to thank all the staff of the Oncology Department of Ibn Rochd University Hospital and the Genetic and Molecular Pathology Laboratory for their collaboration.

Conflicts of interest

The authors have no conflicts of interest to declare.


  1. 1.
    Bonadona V, Lasset C. Inherited predisposition to breast cancer: after the BRCA1 and BRCA2 genes, what next? Bull Cancer. 2003;90:587–4.PubMedGoogle Scholar
  2. 2.
    Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–10.PubMedCrossRefGoogle Scholar
  3. 3.
    Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;12:909–23.CrossRefGoogle Scholar
  4. 4.
    Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, et al. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet. 2007;39:776–80.PubMedCrossRefGoogle Scholar
  5. 5.
    Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007;8:275–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Van der Groep P, Van der Wall E, Van Diest PJ. Pathology of hereditary breast cancer. Cell Oncol. 2011;34:71–88.CrossRefGoogle Scholar
  7. 7.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253:49–53.PubMedCrossRefGoogle Scholar
  8. 8.
    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;396:85–9.PubMedCrossRefGoogle Scholar
  9. 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;14:3503–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Chompret A, Brugières L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000;82:1932–7.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Whibley C, Pharoah PD, Hollstein M. p53 polymorphisms: cancer implications. Nat Rev Cancer. 2009;9:95–107.PubMedCrossRefGoogle Scholar
  12. 12.
    Guleria K, Sharma S, Manjari M, Singh Uppal M, Rajan Singh N, Sambyal V. P.R72P, PIN3 Ins16bp polymorphisms of TP53 and CCR5Δ32 in north Indian breast cancer patients. Asian Pac J Cancer Prev. 2012;13:3305–11.PubMedCrossRefGoogle Scholar
  13. 13.
    Roy AG, Sarkar B, Roy R, Rao V, Bandyopadhyay A. Absence of p53 gene mutations in exons 5–7 among breast cancer patients of Bengalee Hindu caste females, West Bengal India. Asian Pac J Cancer Prev. 2012;13:4477–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Vijayaraman KP, Veluchamy M, Murugesan P, Shanmugiah KP, Kasi PD. p53 exon 4 (codon 72) polymorphism and exon 7 (codon 249) mutation in breast cancer patients in southern region (Madurai) of Tamil Nadu. Asian Pac J Cancer Prev. 2012;13:511–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Lehman TA, Haffty BG, Carbone CJ, Bishop LR, Gumbs AA, Krishnan S, et al. Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer. Cancer Res. 2000;60:1062–9.PubMedGoogle Scholar
  16. 16.
    Gemignani F, Moreno V, Landi S, Moullan N, Chabrier A, Gutiérrez-Enriquez S, et al. A TP53 polymorphism is associated with increased risk of colorectal cancer and with reduced levels of TP53 mRNA. Oncogene. 2004;23:1954–6.PubMedCrossRefGoogle Scholar
  17. 17.
    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;94:681–90.PubMedCrossRefGoogle Scholar
  18. 18.
    Runnebaum IB, Tong XW, König R, Zhao H, Körner K, Atkinson EN, et al. p53-based blood test for p53PIN3 and risk for sporadic ovarian cancer. Lancet. 1995;345:994.PubMedCrossRefGoogle Scholar
  19. 19.
    Costa S, Pinto D, Pereira D, Rodrigues H, Cameselle-Teijeiro J, Medeiros R, et al. Importance of TP53 codon 72 and intron 3 duplication 16bp polymorphisms in prediction of susceptibility on breast cancer. BMC Cancer. 2008;8:32.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Malik MA, Sharma K, Goel S, Zargar SA, Mittal B. Association of TP53 intron 3, 16bp duplication polymorphism with esophageal and gastric cancer susceptibility in Kashmir Valley. Oncol Res. 2011;19:165–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Hu Z, Li X, Qu X, He Y, Ring BZ, Song E, et al. Intron 3 16bp duplication polymorphism of TP53 contributes to cancer susceptibility: a meta-analysis. Carcinogenesis. 2010;31:643–7.PubMedCrossRefGoogle Scholar
  22. 22.
    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;130:517–29.PubMedCrossRefGoogle Scholar
  23. 23.
    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;4:492.CrossRefGoogle Scholar
  24. 24.
    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;8:61662.CrossRefGoogle Scholar
  25. 25.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.PubMedCrossRefGoogle Scholar
  26. 26.
    Bouchbika Z, Haddad H, Benchakroun N, Eddakaoui H, Kotbi S, Megrini A, et al. Cancer incidence in Morocco: report from Casablanca registry 2005-2007. Pan Afr Med J. 2013;16:31.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Tazi MA, Er-Raki A, Benjaafar N. Cancer incidence in Rabat, Morocco: 2006-2008. Ecancer. 2013;7:338.Google Scholar
  28. 28.
    Hamdi Cherif M, Zaidi Z, Abdellouche D, Hamdi S, Lakhdari N, Djema BA. Registre du cancer de Sétif (Algérie): incidence, tendance et survie, 1986–2005. J Afr Cancer. 2010;2:245–58.CrossRefGoogle Scholar
  29. 29.
    Ben Abdallah M, Zehani S, Maalej M, Hsairi M, Hechiche M, Ben Romdhane K, et al. Cancer du sein en Tunisie: caractéristiques épidémiologiques et tendance évolutive de l'incidence. Tunis Med. 2009;87:417–25.PubMedGoogle Scholar
  30. 30.
    El Mistiri M, Pirani M, El Sahli N, El Mangoush M, Attia A, Shembesh R, et al. Cancer profile in eastern Libya: incidence and mortality in the year 2004. Ann Oncol. 2010;21:1924–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Marrett LD, De P, Airia P, Dryer D. Cancer in Canada in 2008. CMAJ. 2008;179:1163–70.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Botha JL, Bray F, Sankila R, Parkin DM. Breast cancer incidence and mortality trends in 16 European countries. Eur J Cancer. 2003;39:1718–29.PubMedCrossRefGoogle Scholar
  33. 33.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRefGoogle Scholar
  34. 34.
    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Brankovic-Magic MV, Jankovic RN, Dobricic JD, Borojevic ND, Magic ZM, Radulovic SS. TP53 mutations in breast cancer: association with ductal histology and early relapse of disease. Int J Biol Markers. 2008;23:147–53.PubMedGoogle Scholar
  36. 36.
    Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, et al. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993;362:849–52.PubMedCrossRefGoogle Scholar
  37. 37.
    Kulesz-Martin MF, Lisafeld B, Huang H, Kisiel ND, Lee L. Endogenous p53 protein generated from wild-type alternatively spliced p53 RNA in mouse epidermal cells. Mol Cell Biol. 1994;14:1698–708.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Puisieux A, Lim S, Groopman J, Ozturk M. Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens. Cancer Res. 1991;51:6185–9.PubMedGoogle Scholar
  39. 39.
    Pavletich NP, Chambers KA, Pabo CO. The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. Genes Dev. 1993;7:2556–64.PubMedCrossRefGoogle Scholar
  40. 40.
    Chang F, Syrjänen S, Kurvinen K, Syrjänen K. The p53 tumor suppressor gene as a common cellular target in human carcinogenesis. Am J Gastroenterol. 1993;88:174–86.PubMedGoogle Scholar
  41. 41.
    Harris CC, Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med. 1993;329:1318–27.PubMedCrossRefGoogle Scholar
  42. 42.
    Wang-Gohrke S, Becher H, Kreienberg R, Runnebaum IB, Chang-Claude J. Intron 3 16bp duplication polymorphism of p53 is associated with an increased risk for breast cancer by the age of 50 years. Pharmacogenetics. 2002;12:269–72.PubMedCrossRefGoogle Scholar
  43. 43.
    Bisof V et al. TP53 gene polymorphisms and breast cancer in Croatian women: a pilot study. Eur J Gynaecol Oncol. 2010;31:539–44.PubMedGoogle Scholar
  44. 44.
    Faghani M, Ghasemi FM, Nikhbakht M, Salehi M. TP53 PIN3 polymorphism associated with breast cancer risk in Iranian women. Indian J Cancer. 2011;48:298–302.PubMedCrossRefGoogle Scholar
  45. 45.
    Peller S, Kopilova Y, Slutzki S, Halevy A, Kvitko K, Rotter V. A novel polymorphism in intron 6 of the human p53 gene: a possible association with cancer predisposition and susceptibility. DNA Cell Biol. 1995;14:983–90.PubMedCrossRefGoogle Scholar
  46. 46.
    Weston A, Pan CF, Ksieski HB, Wallenstein S, Berkowitz GS, Tartter PI, et al. p53 haplotype determination in breast cancer. Cancer Epidemiol Biomark Prev. 1997;6:105–12.Google Scholar
  47. 47.
    Suspitsin EN, Buslov KG, Grigoriev MY, Ishutkina JG, Ulibina JM, Gorodinskaya VM, et al. Evidence against involvement of p53 polymorphism in breast cancer predisposition. Int J Cancer. 2003;103:431–3.PubMedCrossRefGoogle Scholar
  48. 48.
    Fiszer-Maliszewska Ł, Kazanowska B, Kuśnierczyk P, Mańczak M, Niepiekło W, Pochroń-Zeman B, et al. Is p53 intronic variant G13964C associated with predisposition to cancer? J Appl Genet. 2004;44:547–52.Google Scholar
  49. 49.
    Buyru N, Altinisik J, Demokan S, Dalay N. p53 genotypes and haplotypes associated with risk of breast cancer. Cancer Detect Prev. 2007;31:207–13.PubMedCrossRefGoogle Scholar
  50. 50.
    De Vecchi G, Verderio P, Pizzamiglio S, Manoukian S, Bernard L, Pensotti V, et al. The p53 Arg72Pro and Ins16 bp polymorphisms and their haplotypes are not associated with breast cancer risk in BRCA-mutation negative familial cases. Cancer Detect Prev. 2008;32:140–3.PubMedCrossRefGoogle Scholar
  51. 51.
    Cavallone L, Arcand SL, Maugard C, Ghadirian P, Mes-Masson AM, Provencher D, et al. Haplotype analysis of TP53 polymorphisms, Arg72Pro and Ins16, in BRCA1 and BRCA2 mutation carriers of French Canadian descent. BMC Cancer. 2008;8:96.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Trifa F, Karray-Chouayekh S, Mabrouk I, Baccouche S, Khabir A, Sellami-Boudawara T, et al. Haplotype analysis of p53 polymorphisms: Arg72Pro, Ins16 bp and G13964C in Tunisian patients with familial or sporadic breast cancer. Cancer Epidemiol. 2010;34:184–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Pouladi N, Kouhsari SM, Feizi MH, Dehghan R, Azarfam P, Farajzadeh D. Lack of association of intron 3 16bp polymorphism of TP53 with breast cancer among Iranian-Azeri patients. Asian Pac J Cancer Prev. 2014;15:2631–4.PubMedCrossRefGoogle Scholar
  54. 54.
    Akkiprik M, Sonmez O, Gulluoglu BM, Caglar HB, Kaya H, Demirkalem P, et al. Analysis of p53 gene polymorphisms and protein over-expression in patients with breast cancer. Pathol Onco Res. 2009;15:359–68.CrossRefGoogle Scholar
  55. 55.
    Osorio A, Pollán M, Pita G, Schmutzler RK, Versmold B, Engel C, et al. CIMBA. An evaluation of the polymorphisms Ins16bp and Arg72Pro in p53 as breast cancer risk modifiers in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2008;99:974–7.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Alawadi S, Ghabreau L, Alsaleh M, Abdulaziz Z, Rafeek M, Akil N, et al. P53 gene polymorphisms and breast cancer risk in Arab women. Med Oncol. 2011;28:709–15.PubMedCrossRefGoogle Scholar
  57. 57.
    Khaliq S, Hameed A, Khaliq T, Ayub Q, Qamar R, Mohyuddin A, et al. P53 mutations, polymorphisms, and haplotypes in Pakistani ethnic groups and breast cancer patients. Genet Test. 2000;4:23–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Mahasneh AA, Abdel-Hafiz SS. Polymorphism of p53 gene in Jordanian population and possible associations with breast cancer and lung adenocarcinoma. Saudi Med J. 2004;25:1568–73.PubMedGoogle Scholar
  59. 59.
    Wang-Gohrke S, Rebbeck TR, Besenfelder W, Kreienberg R, Runnebaum IB. p53 germline polymorphisms are associated with an increased risk for breast cancer in German women. Anticancer Res. 1998;18:2095–9.PubMedGoogle Scholar
  60. 60.
    Olden K, Freudenberg N, Dowd J, Shields AE. Discovering how environmental exposures alter genes could lead to new treatments for chronic illnesses. Health Aff (Millwood). 2011;30:833–41.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Chaymaa Marouf
    • 1
    • 3
  • Amal Tazzite
    • 1
  • Brehima Diakité
    • 1
  • Hassan Jouhadi
    • 2
  • Abdellatif Benider
    • 2
  • Sellama Nadifi
    • 1
  1. 1.Genetics and Molecular Pathology Laboratory, Medical School of CasablancaUniversity Hassan IICasablancaMorocco
  2. 2.Mohammed VI Center for Cancer TreatmentIbn Rochd University HospitalCasablancaMorocco
  3. 3.HeidelbergGermany

Personalised recommendations