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Association between polymorphisms in apoptotic genes and susceptibility for developing breast cancer in Syrian women

  • Epidemiology
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Abstract

Apoptosis is a major protective mechanism against cancer. The tumor suppressor protein p53 is the central protein in the apoptotic pathway and was shown to harbor mutations in a considerable fraction of breast cancer tumors. The NQO1 was shown to act as a p53 stabilizer and was suggested to play an important role in the protection against carcinogenic catechol estrogens. Functional polymorphisms in TP53 and NQO1 were investigated in relation to breast cancer susceptibility in several studies, primarily involving Asian and Caucasian populations. The aim of the present study was to investigate TP53 and NQO1 polymorphisms and their combined effects with respect to breast cancer susceptibility in a Syrian study cohort. The study cohort consisted of 122 cases and 139 controls. The tetra-primer ARMS-PCR method was used to genotype three TP53 polymorphisms; namely, exon 4 G>C Arg72Pro, IVS3 16 bp Del/Ins, and MspI IVS6+62A>G, and NQO1 C609T (Pro187Ser) polymorphism. Association was tested under six genetic models. We found a significant association for the heterozygous Arg/Pro genotype when combined with heterozygosity for IVS3 16 bp Del/Ins and MspI IVS6+62A>G (OR = 2.05 (1.22–3.47), P = 0.006). No significant association was found for NQO1 C609T or its combinations with TP53 polymorphisms. Our results support an association for TP53 polymorphisms with breast cancer susceptibility in the Syrian population.

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References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM.GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010

  2. Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, Mulvihill JJ (1989) Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81(24):1879–1886

    Article  PubMed  CAS  Google Scholar 

  3. el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B (1992) Definition of a consensus binding site for p53. Nat Gene 1(1):45–49

    Article  CAS  Google Scholar 

  4. Roy B, Beamon J, Balint E, Reisman D (1994) Transactivation of the human p53 tumor suppressor gene by c-Myc/Max contributes to elevated mutant p53 expression in some tumors. Mol Cell Biol 14(12):7805–7815

    PubMed  CAS  Google Scholar 

  5. Pavletich NP, Chambers KA, Pabo CO (1993) The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. Genes Dev 7(12B):2556–2564

    Article  PubMed  CAS  Google Scholar 

  6. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A et al (2011) COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Res 39(Database issue):D945–D950

    Article  PubMed  CAS  Google Scholar 

  7. Asher G, Lotem J, Cohen B, Sachs L, Shaul Y (2001) Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proc Natl Acad Sci USA 98(3):1188–1193

    Article  PubMed  CAS  Google Scholar 

  8. Bianco NR, Perry G, Smith MA, Templeton DJ, Montano MM (2003) Functional implications of antiestrogen induction of quinone reductase: inhibition of estrogen-induced deoxyribonucleic acid damage. Mol Endocrinol 17(7):1344–1355

    Article  PubMed  CAS  Google Scholar 

  9. Huang XE, Hamajima N, Katsuda N, Matsuo K, Hirose K, Mizutani M, Iwata H, Miura S, Xiang J, Tokudome S et al (2003) Association of p53 codon Arg72Pro and p73 G4C14-to-A4T14 at exon 2 genetic polymorphisms with the risk of Japanese breast cancer. Breast Cancer 10(4):307–311

    Article  PubMed  Google Scholar 

  10. Weston A, Pan CF, Ksieski HB, Wallenstein S, Berkowitz GS, Tartter PI, Bleiweiss IJ, Brower ST, Senie RT, Wolff MS (1997) p53 haplotype determination in breast cancer. Cancer Epidemiol Biomarkers Prev 6(2):105–112

    PubMed  CAS  Google Scholar 

  11. Buyru N, Tigli H, Dalay N (2003) P53 codon 72 polymorphism in breast cancer. Oncol Rep 10(3):711–714

    PubMed  CAS  Google Scholar 

  12. Ohayon T, Gershoni-Baruch R, Papa MZ, Distelman Menachem T, Eisenberg Barzilai S, Friedman E (2005) The R72P P53 mutation is associated with familial breast cancer in Jewish women. Br J Cancer 92(6):1144–1148

    Article  PubMed  CAS  Google Scholar 

  13. Damin AP, Frazzon AP, Damin DC, Roehe A, Hermes V, Zettler C, Alexandre CO (2006) Evidence for an association of TP53 codon 72 polymorphism with breast cancer risk. Cancer Detect Prev 30(6):523–529

    Article  PubMed  CAS  Google Scholar 

  14. Menzel HJ, Sarmanova J, Soucek P, Berberich R, Grunewald K, Haun M, Kraft HG (2004) Association of NQO1 polymorphism with spontaneous breast cancer in two independent populations. Br J Cancer 90(10):1989–1994

    Article  PubMed  CAS  Google Scholar 

  15. Aston CE, Ralph DA, Lalo DP, Manjeshwar S, Gramling BA, DeFreese DC, West AD, Branam DE, Thompson LF, Craft MA et al (2005) Oligogenic combinations associated with breast cancer risk in women under 53 years of age. Hum Genet 116(3):208–221

    Article  PubMed  CAS  Google Scholar 

  16. Hong CC, Ambrosone CB, Ahn J, Choi JY, McCullough ML, Stevens VL, Rodriguez C, Thun MJ, Calle EE (2007) Genetic variability in iron-related oxidative stress pathways (Nrf2, NQ01, NOS3, and HO-1), iron intake, and risk of postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 16(9):1784–1794

    Article  PubMed  CAS  Google Scholar 

  17. Sarmanova J, Susova S, Gut I, Mrhalova M, Kodet R, Adamek J, Roth Z, Soucek P (2004) Breast cancer: role of polymorphisms in biotransformation enzymes. Eur J Hum Genet 12(10):848–854

    Article  PubMed  CAS  Google Scholar 

  18. Siegelmann-Danieli N, Buetow KH (2002) Significance of genetic variation at the glutathione S-transferase M1 and NAD(P)H: quinone oxidoreductase 1 detoxification genes in breast cancer development. Oncology 62(1):39–45

    Article  PubMed  CAS  Google Scholar 

  19. Alawadi S, Ghabreau L, Alsaleh M, Abdulaziz Z, Rafeek M, Akil N, Alkhalaf M (2011) P53 gene polymorphisms and breast cancer risk in Arab women. Med Oncol 28(3):709–715

    Article  PubMed  Google Scholar 

  20. Trifa F, Karray-Chouayekh S, Mabrouk I, Baccouche S, Khabir A, Sellami-Boudawara T, Gargouri A, Mokdad-Gargouri R (2010) Haplotype analysis of p53 polymorphisms: Arg72Pro, Ins16 bp and G13964C in Tunisian patients with familial or sporadic breast cancer. Cancer Epidemiol 34(2):184–188

    Article  PubMed  CAS  Google Scholar 

  21. Lajin B, Alachkar A, Alhaj Sakur A (2012) A quadruplex tetra-primer ARMS-PCR method for the simultaneous detection of TP53 Arg72Pro, IVS3 16 bp Del/Ins and IVS6+62A>G, and NQO1 C609T polymorphisms. Gene 504(2):268–273

    Article  PubMed  CAS  Google Scholar 

  22. Slatkin M, Excoffier L (1996) Testing for linkage disequilibrium in genotypic data using the expectation-maximization algorithm. Heredity 76(Pt 4):377–383

    Article  PubMed  Google Scholar 

  23. Yoo J, Lee Y, Kim Y, Rha SY, Kim Y (2008) SNPAnalyzer 2.0: a web-based integrated workbench for linkage disequilibrium analysis and association analysis. BMC Bioinform 9:290

    Article  Google Scholar 

  24. Dumont P, Leu JI, Della Pietra AC 3rd, George DL, Murphy M (2003) The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33(3):357–365

    Article  PubMed  CAS  Google Scholar 

  25. Brooks LA, Tidy JA, Gusterson B, Hiller L, O’Nions J, Gasco M, Marin MC, Farrell PJ, Kaelin WG Jr, Crook T (2000) Preferential retention of codon 72 arginine p53 in squamous cell carcinomas of the vulva occurs in cancers positive and negative for human papillomavirus. Cancer Res 60(24):6875–6877

    PubMed  CAS  Google Scholar 

  26. Schneider-Stock R, Mawrin C, Motsch C, Boltze C, Peters B, Hartig R, Buhtz P, Giers A, Rohrbeck A, Freigang B et al (2004) Retention of the arginine allele in codon 72 of the p53 gene correlates with poor apoptosis in head and neck cancer. Am J Pathol 164(4):1233–1241

    Article  PubMed  CAS  Google Scholar 

  27. Kawaguchi H, Ohno S, Araki K, Miyazaki M, Saeki H, Watanabe M, Tanaka S, Sugimachi K (2000) p53 polymorphism in human papillomavirus-associated esophageal cancer. Cancer Res 60(11):2753–2755

    PubMed  CAS  Google Scholar 

  28. Schneider-Stock R, Boltze C, Peters B, Szibor R, Landt O, Meyer F, Roessner A (2004) Selective loss of codon 72 proline p53 and frequent mutational inactivation of the retained arginine allele in colorectal cancer. Neoplasia 6(5):529–535

    Article  PubMed  CAS  Google Scholar 

  29. Marin MC, Jost CA, Brooks LA, Irwin MS, O’Nions J, Tidy JA, James N, McGregor JM, Harwood CA, Yulug IG et al (2000) A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nat Genet 25(1):47–54

    Article  PubMed  CAS  Google Scholar 

  30. van Duin M, Snijders PJ, Vossen MT, Klaassen E, Voorhorst F, Verheijen RH, Helmerhorst TJ, Meijer CJ, Walboomers JM (2000) Analysis of human papillomavirus type 16 E6 variants in relation to p53 codon 72 polymorphism genotypes in cervical carcinogenesis. J Gen Virol 81(Pt 2):317–325

    PubMed  Google Scholar 

  31. Peller S, Halperin R, Schneider D, Kopilova Y, Rotter V (1999) Polymorphisms of the p53 gene in women with ovarian or endometrial carcinoma. Oncol Rep 6(1):193–197

    PubMed  CAS  Google Scholar 

  32. Storey A, Thomas M, Kalita A, Harwood C, Gardiol D, Mantovani F, Breuer J, Leigh IM, Matlashewski G, Banks L (1998) Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 393(6682):229–234

    Article  PubMed  CAS  Google Scholar 

  33. Hu Z, Li X, Qu X, He Y, Ring BZ, Song E, Su L (2010) Intron 3 16 bp duplication polymorphism of TP53 contributes to cancer susceptibility: a meta-analysis. Carcinogenesis 31(4):643–647

    Article  PubMed  CAS  Google Scholar 

  34. Gemignani F, Moreno V, Landi S, Moullan N, Chabrier A, Gutierrez-Enriquez S, Hall J, Guino E, Peinado MA, Capella G et al (2004) A TP53 polymorphism is associated with increased risk of colorectal cancer and with reduced levels of TP53 mRNA. Oncogene 23(10):1954–1956

    Article  PubMed  CAS  Google Scholar 

  35. He XF, Su J, Zhang Y, Huang X, Liu Y, Ding DP, Wang W, Arparkorn K (2011) Association between the p53 polymorphisms and breast cancer risk: meta-analysis based on case-control study. Breast Cancer Res Treat 130(2):517–529

    Article  PubMed  CAS  Google Scholar 

  36. Nikbakht Dastjerdi M, Mirmohammad SH (2010) TP53 codon 72 heterozygosity may promote microsatellite instability in sporadic colorectal cancer. YAKHTEH 12:1–6

    Google Scholar 

  37. Toyama T, Iwase H, Yamashita H, Iwata H, Yamashita T, Ito K, Hara Y, Suchi M, Kato T, Nakamura T et al (1996) Microsatellite instability in sporadic human breast cancers. Int J Cancer 68(4):447–451

    Article  PubMed  CAS  Google Scholar 

  38. Anbazhagan R, Fujii H, Gabrielson E (1999) Microsatellite instability is uncommon in breast cancer. Clin Cancer Res 5(4):839–844

    PubMed  CAS  Google Scholar 

  39. Akil N, Yasmeen A, Kassab A, Ghabreau L, Darnel AD, Al Moustafa AE (2008) High-risk human papillomavirus infections in breast cancer in Syrian women and their association with Id-1 expression: a tissue microarray study. Br J Cancer 99(3):404–407

    Article  PubMed  CAS  Google Scholar 

  40. Kim JW, Lee CG, Park YG, Kim KS, Kim IK, Sohn YW, Min HK, Lee JM, Namkoong SE (2000) Combined analysis of germline polymorphisms of p53, GSTM1, GSTT1, CYP1A1, and CYP2E1: relation to the incidence rate of cervical carcinoma. Cancer 88(9):2082–2091

    Article  PubMed  CAS  Google Scholar 

  41. Klug SJ, Wilmotte R, Santos C, Almonte M, Herrero R, Guerrero I, Caceres E, Peixoto-Guimaraes D, Lenoir G, Hainaut P et al (2001) TP53 polymorphism, HPV infection, and risk of cervical cancer. Cancer Epidemiol Biomarkers Prev 10(9):1009–1012

    PubMed  CAS  Google Scholar 

  42. Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, Ross D (2001) Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H: quinone oxidoreductase 1. Mol Pharmacol 59(2):263–268

    PubMed  CAS  Google Scholar 

  43. Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69(7):1237–1245

    Article  PubMed  CAS  Google Scholar 

  44. Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119(5):591–602

    Article  PubMed  CAS  Google Scholar 

  45. Singh V, Upadhyay G, Rastogi N, Singh K, Singh MP (2011) Polymorphism of xenobiotic-metabolizing genes and breast cancer susceptibility in North Indian women. Genet Test Mol Biomarkers 15(5):343–349

    Article  PubMed  CAS  Google Scholar 

  46. Hamajima N, Matsuo K, Iwata H, Shinoda M, Yamamura Y, Kato T, Hatooka S, Mitsudomi T, Suyama M, Kagami Y et al (2002) NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism and the risk of eight cancers for Japanese. Int J Clin Oncol 7(2):103–108

    PubMed  CAS  Google Scholar 

  47. Fowke JH, Shu XO, Dai Q, Jin F, Cai Q, Gao YT, Zheng W (2004) Oral contraceptive use and breast cancer risk: modification by NAD(P)H: quinone oxoreductase (NQO1) genetic polymorphisms. Cancer Epidemiol Biomarkers Prev 13(8):1308–1315

    PubMed  CAS  Google Scholar 

  48. Yuan W, Xu L, Chen W, Wang L, Fu Z, Pang D, Li D (2011) Evidence on the association between NQO1 Pro187Ser polymorphism and breast cancer risk in the current studies: a meta-analysis. Breast Cancer Res Treat 125(2):467–472

    Article  PubMed  Google Scholar 

  49. Al-Qasem A, Toulimat M, Tulbah A, Elkum N, Al-Tweigeri T, Aboussekhra A (2012) The p53 codon 72 polymorphism is associated with risk and early onset of breast cancer among Saudi women. Oncol Lett 3(4):875–878

    PubMed  CAS  Google Scholar 

  50. Beckman G, Birgander R, Sjalander A, Saha N, Holmberg PA, Kivela A, Beckman L (1994) Is p53 polymorphism maintained by natural selection? Hum Hered 44(5):266–270

    Article  PubMed  CAS  Google Scholar 

  51. Al-Qasem AJ, Toulimat M, Eldali AM, Tulbah A, Al-Yousef N, Al-Daihan SK, Al-Tassan N, Al-Tweigeri T, Aboussekhra A (2011) TP53 genetic alterations in Arab breast cancer patients: novel mutations, pattern and distribution. Oncol Lett 2(2):363–369

    PubMed  CAS  Google Scholar 

  52. Wu X, Zhao H, Amos CI, Shete S, Makan N, Hong WK, Kadlubar FF, Spitz MR (2002) p53 genotypes and haplotypes associated with lung cancer susceptibility and ethnicity. J Natl Cancer Inst 94(9):681–690

    Article  PubMed  CAS  Google Scholar 

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Lajin, B., Alhaj Sakur, A. & Alachkar, A. Association between polymorphisms in apoptotic genes and susceptibility for developing breast cancer in Syrian women. Breast Cancer Res Treat 138, 611–619 (2013). https://doi.org/10.1007/s10549-013-2467-4

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