Determination of the predictive and prognostic values of polymorphism of some cell cycle genes in breast cancer

  • Authors

    • Samia Ebeid Prof in Department of applied medical chemistry
    • Nadia Abd El Moneim Prof in Department of Cancer Management and Research
    • Taha Hewala Ass. Prof and the head of Radiation Sciences DepartmentMedical Research Institute - Alexandria University165 El-Horreya Avenue, El- HadraPOB: 21561, Alexandria, Egypt
    • Moustafa Ramadan lecturer in Department of experimental and clinical surgery
    • Gehan Shehata Lecturer in Department of Bioinformatics and Medical Statistics
    • Heba Abass
    2016-05-22
    https://doi.org/10.14419/ijbas.v5i2.6047
  • Breast Cancer, Polymorphism, CCND1 (G870A), P73 (G4C14-to- A4T14), Risk, Diagnosis, Prognosis

  • Aim: To investigate the influence of the polymorphic variants of CCND1 (G870A) and p73 (G4C14- to- A4T14) on the susceptibility to breast cancer development, also, to figure out their diagnostic and prognostic roles.

    Subjects and Methods: Blood samples were obtained from breast cancer patients and controls. Genotyping of CCND1 and p73 genes were carried out by PCR-RFLP and PCR-CTPP; respectively.

    Results: In comparison with the control group, CCND1 (G870A) GA and AA genotypes frequencies were significantly higher in breast cancer patients (p=0.035 and p=0.002; respectively), whereas CCND1 (G870A) GG genotype frequency was significantly lower (p< 0.001). The CCND1 GA and AA genotypes significantly increased the risk for developing breast cancer compared with the GG genotype. The CCND1 (GA+AA) genotypes were significantly correlated with disease-free survival (DFS) of breast cancer patients. In comparison with the control group, p73 (G4C14/A4T14) GC/AT and AT/AT genotypes frequencies were significantly higher in breast cancer patients (p=0.013 and p=0.04; respectively), whereas p73 (G4C14/A4T14) GC/GC genotype frequency was significantly lower (p= 0.004).  Compared with the GC/GC genotype, the p73 GC/AT and AT/AT genotypes significantly increased the risk for developing breast cancer. Beside being significantly correlated with DFS, p73 [(GC/AT)+ (AT/AT)] genotypes were indirectly correlated with tumor size, tumor pathological grade, patient's clinical stage, number of axillary lymph node involvement and Her2/neu expression.

    Conclusion: The GA and AA genotypes of CCND1 (G870A) polymorphism and the GC/AT and AT/AT genotypes of p73 (G4C14- to- A4T14) polymorphism can be used as diagnostic markers in breast cancer patients. The presence of the CCND1 (G870A) GA and AA genotypes and the GC/AT and AT/AT genotypes of p73 (G4C14- to- A4T14) polymorphism can increase the susceptibility to breast cancer incidence. Both of CCND1 (G870A) and p73 (G4C14- to- A4T14) polymorphisms can be used for prognosis of breast cancer patients. 

  • References

    1. [1] Lee K-M, Han S, Park W-Y, Kang D. Identification and application of biomarkers in molecular and genomic epidemiologic research. J Prev Med Public Health 2009; 42: 349-55. http://dx.doi.org/10.3961/jpmph.2009.42.6.349.

      [2] Kwan ML, Kushi LH, Weltzien E, Maring B, Kutner SE, Fulton RS, et al. Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors. Breast Cancer Res 2009; 1: R31-43. http://dx.doi.org/10.1186/bcr2261.

      [3] Sadikovic B, Al-Romaih K, Squire JA, Zielenska M. Cause and consequences of genetic and epigenetic alterations in human cancer. Curr Genomics 2008; 9:394-408. http://dx.doi.org/10.2174/138920208785699580.

      [4] Sherr CJ. D-type cyclins. Trends Biochem Sci 1995; 20:187–90. http://dx.doi.org/10.1016/S0968-0004(00)89005-2.

      [5] Lin DI, Barbash O, Kumar KGS, Weber JD, Harper JW, Klein-Szanto AJP, et al. Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF (FBX4-alphaB crystallin) complex. Mol Cell 2006; 24:355–66. http://dx.doi.org/10.1016/j.molcel.2006.09.007.

      [6] Diehl JA, Zindy F, Sherr CJ. Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev. 1997; 11:957–72. http://dx.doi.org/10.1101/gad.11.8.957.

      [7] Betticher DC, Thatcher N, Altermatt HJ, Hoban P, Ryder WD, Heighway J. Alternate splicing produces a novel cyclin D1 transcript. Oncogene 1995; 11:1005–11.

      [8] Solomon DA, Wang Y, Fox SR, Lambeck TC, Giesting S, Lan Z, et al. Cyclin D1 splice variants. Differential effects on localization, RB phosphorylation, and cellular transformation. J Biol Chem 2003; 278:30339–47. http://dx.doi.org/10.1074/jbc.M303969200.

      [9] Shu XO, Moore DB, Cai Q, Cheng J, Wen W, Pierce L, et al. Association of cyclin D1 genotype with breast cancer risk and survival. Cancer Epidemiol Biomarkers Prev 2005; 14: 91-7.

      [10] Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, et al. The G870A polymorphism of the cyclin D1 gene is not associated with breast cancer. Breast Cancer Res Treat 2003; 82: 165-8.

      http://dx.doi.org/10.1023/B:BREA.0000004372.20461.33.

      [11] Onay UV, Aaltonen K, Briollais L, Knight JA, Pabalan N, Kilpivaara O, et al. Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk. BMC Cancer 2008; 8: 6. http://dx.doi.org/10.1186/1471-2407-8-6.

      [12] Yu CP, Yu JC, Sun CA, Tzao C, Ho JY, Yen AM. Tumor susceptibility and prognosis of breast cancer associated with the G870A polymorphism of CCND1. Breast Cancer Res Treat 2008; 107: 95-102. http://dx.doi.org/10.1007/s10549-007-9522-y.

      [13] Lu C, Dong J, Ma H, Jin G, Hu Z, Peng Y, et al. CCND1 (G870A) polymorphism contributes to breast cancer susceptibility: a meta-analysis. Breast Cancer Res Treat 2009; 116: 571-5. http://dx.doi.org/10.1007/s10549-008-0195-y.

      [14] Bedewy AML, Mostafa MH, Saad AA, EL-Maghraby SM, Bedewy MML, Hilal AM, et al. Association of Cyclin D1 A870G polymorphism with two malignancies: Acute lymphoblastic leukemia and breast cancer. J BUON 2013; 18: 227-38.

      [15] Moll UM, Slade N. P63 and p73: roles in development and tumor formation. Mol Cancer Res 2004; 2: 371-86.

      [16] Jost C A, Marin M C, Kaelin W G. P73 is a simian p53-related protein that can induce apoptosis. Nature 1997; 389: 191–4. http://dx.doi.org/10.1038/38298.

      [17] De Feo E, Persiani R, La Greca A, Amore R, Arzani D, Rausei S, et al. A case-control study on the effect of p53 and p73 gene polymorphisms on gastric cancer risk and progression. Mutat Res 2009; 30: 60-5. http://dx.doi.org/10.1016/j.mrgentox.2009.02.009.

      [18] Niwa Y, Hirose K, Matsuo K, Tajima K, Ikoma Y, Nakanishi T. Association of p73 (G4C14-to-A4T14) polymorphism at exon 2 and p53 (Arg72Pro) polymorphism with the risk of endometrial cancer in Japanese subjects. Cancer Lett 2005; 219: 183–90. http://dx.doi.org/10.1016/j.canlet.2004.10.018.

      [19] Huang XE, Hamajima N, Katsuda N, Matsuo K, Hirose K, Mizutani M. et al. Association of p53 codon Arg72Pro and p73 G4C14-to-A4T14 at exon 2 genetic polymorphisms with the risk of Japanese breast cancer. Breast Cancer 2003; 10: 307-11. http://dx.doi.org/10.1007/BF02967650.

      [20] Liu F, Liu L, Li B, Wei Y, Yan L, Wen T, et al. p73 (G4C14-A4T14) polymorphism and cancer risk: a meta-analysis based on 27 case–control studies. Mutagenesis 2011; 26:573–81. http://dx.doi.org/10.1093/mutage/ger018.

      [21] Haskell CM, Lowitz BB, Casciato AD. Breast cancer. In: Casciato AD and Lowitz BB; eds. Manual of clinical oncology; 2nd ed. little and Brown Company, Boston, Toronto (pub.) 1985, pp. 150-65.

      [22] Rintoul RF. Operations on the breast. In: Farquhaerison,s text book of operative surgery; 7th ed. Churchill living stone (pub.) 1986, pp. 270-81.

      [23] Abeloff MD, Lichter AS, Niederhuber JE, Pierce LJ and Aziz DC. Breast. In: Abeloff MD, Armitage JO, Licher AS, Niederhuber JE; eds. Clinical Oncology, Churchil living stone Inc. (Pub.), 1995, Chapter 73, pp 1617-714.

      [24] Wang L, Habuchi T, Takahashi T, Mitsumori K, Kamoto T, Kakehi Y, et al. Cyclin D1 gene polymorphism is associated with an increased risk of urinary bladder cancer. Carcinogenesis 2002; 23: 257-64. http://dx.doi.org/10.1093/carcin/23.2.257.

      [25] Hamajima N, Tamakoshi A, Kawase H, Wakai K, Katsuda N, Saito T, et al. Duplex polymerase chain reaction with confronting two-pair primers (PCR-CTTP) for genotyping alcohol dehydrogenase â subunit (ADH2) and aldehyde dehydrogenase 2(ALDH2). Alcohol & Alcoholism 2003; 38: 407–10. http://dx.doi.org/10.1093/alcalc/agg096.

      [26] Sawa H, Ohshima TA, Ukita H, Murakami H, Chiba Y, Kamada H, et al. Alternatively spliced forms of Cyclin D1 modulate entry into the cell cycle in an inverse manner. Oncogene 1998; 16: 1701-12. http://dx.doi.org/10.1038/sj.onc.1201691.

      [27] Yoylim-Eraltan I, Ergen A, Gormus U, Arikan S, Kucucuk S, Sahin O, et al. Breast cancer and cyclin D gene polymorphism in Turkish women. In vivo 2009; 23:767-72.

      [28] Abramson VG, Troxel AB, Feldman M, Mies C, Wang Y, Sherman L, et al . Cyclin D1b in human breast carcinoma and coexpression with cyclin D1a is associated with poor outcome. Anticancer Res 2010; 30:1279-85.

      [29] Zhou Q, Hopp T, Fuqua SA, Steeg PS. Cyclin D1 in breast premalignancy and early breast cancer: implications for prevention and treatment. Cancer Lett 2001; 162:3 – 17. http://dx.doi.org/10.1016/S0304-3835(00)00657-1.

      [30] Lu F, Gladden AB, Diehl JA. An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer Res 2003; 63: 7056-61.

      [31] Grieu F, Malaney S, Ward R, Joseph D, Iacopetta B. Lack of association between CCND1 (G870A) polymorphism and the risk of breast and colorectal cancers. Anticancer Res 2003; 23: 4257-9.

      [32] Li G, Sturgis EM, Wang L, Chamberlain RM, Amos CI, Spitz MR, et al. Association of a p73 exon 2 G4C14-to-A4T14 polymorphism with risk of squamous cell carcinoma of the head and neck. Carcinogenesis 2004; 25: 1911-6.

      http://dx.doi.org/10.1093/carcin/bgh197.

      [33] Hishida A, Matsuo K, Tajima K, Ogura M, Kagami Y, Taji H. Polymorphisms of p53 Arg72Pro, p73 G4C14-to-A4T14 at exon 2 and p21 Ser31Arg and the risk of non-Hodgkin’s lymphoma in Japanese. Leuk Lymphoma 2004; 45: 957–64. http://dx.doi.org/10.1080/10428190310001638878.

      [34] Ryan BM, McManus R, Daly JS, Carton E, Keeling PW, Reynolds JV. A common p73 polymorphism is associated with a reduced incidence of esophageal carcinoma. Br J Cancer 2001; 85; 1499–503. http://dx.doi.org/10.1054/bjoc.2001.2066.

      [35] Xin Z, Chengyi WU. p73 polymorphisms and clinicopathologic characteristics in breast cancer. J Cent South Univ (Med Sci) 2012; 37: 238-43.

      [36] Du CW, Kimijima I, Otake T, Abe R, Takenoshita S, Zhang GJ. Down-regulation of p73 correlates with high histological grade in Japanese with breast carcinomas. Chin Med J (Engl). 2011; 124:2275-8.

      [37] Daniel Z, Tschan MP, Grob TJ, Peters UR, Fink D, Haenggi W, et al. Differential expression of p73 splice variants and protein in benign and malignant ovarian tumors. Int J Cancer 2000; 88: 66-70. http://dx.doi.org/10.1002/1097-0215(20001001)88:1<66::AID-IJC10>3.0.CO;2-Y.

  • Downloads

  • How to Cite

    Ebeid, S., Abd El Moneim, N., Hewala, T., Ramadan, M., Shehata, G., & Abass, H. (2016). Determination of the predictive and prognostic values of polymorphism of some cell cycle genes in breast cancer. International Journal of Basic and Applied Sciences, 5(2), 157-163. https://doi.org/10.14419/ijbas.v5i2.6047