Tumor Biology

, Volume 37, Issue 5, pp 6905–6912 | Cite as

Influence of BCL2-938 C>A promoter polymorphism and BCL2 gene expression on the progression of breast cancer

  • Phanni bhushann Meka
  • Sarika Jarjapu
  • Sandeep Kumar Vishwakarma
  • Santhoshi Rani Nanchari
  • Anuradha Cingeetham
  • Sandhya Annamaneni
  • Srinivasulu Mukta
  • B. Triveni
  • Vishnupriya Satti
Original Article


BCL2 (B-cell leukemia/lymphoma 2) gene functions as antiapoptotic regulatory element and known to be associated with tumorigenesis. The SNP-938 (C>A) (rs2279115), located in the inhibitory P2 promoter of the BCL2 gene, influences differential binding affinities of transcriptional factors thereby affecting BCL2 expression. The present study is an attempt to evaluate the association between BCL2(-938C>A) polymorphism and clinical characteristics of breast cancer patients as well as to analyze BCL2 expression and Ki67 proliferation index with respect to the genotypes. One hundred ten primary breast cancer tumor tissues were genotyped for -938 C>A polymorphism through PCR-RFLP method as well as evaluated for BCL2 expression and ki67 proliferation index by immunohistochemistry. Evaluation of apoptosis level was performed by flowcytometry. The results revealed that AA genotype was associated with an increased risk (AA Vs AC + CC) by 2.86-fold (p = 0.07) for breast cancer development which reflected in elevated A allele frequency also. AA genotype was found to be predominant among BCL2 positive tumors as compared to BCL2 negative tumors. Further, AA genotype was found to be associated with advanced stage tumors, node positive status, and high Ki67 proliferation index compared to CA and CC genotypes indicating that elevated expression of BCL2 gene in the presence of A allele might be associated with decreased apoptosis and enhanced proliferation rate. AA genotype of BCL2-938C>A polymorphism might influence BCL2 gene expression there by associated with elevated risk for breast cancer progression. Probably, failure of apoptosis due to enhanced expression and antiapoptotic protein BCL2 might promote malignant growth.


BCL2 Apoptosis Immunohistochemistry Ki67 proliferation index Flow cytometry Breast cancer 



We would like to thank MNJ institute of oncology and regional cancer centre, Hyderabad, India for providing samples from breast cancer patients.

Compliance with ethical standards

Conflicts of interest



This study was funded by University Grants Commission-Centre for Advanced Studies (UGC-CAS-II), New Delhi and DBT-OU-ISLARE. Phanni bhushann Meka is thankful to UGC-CAS-II for providing fellowship.


  1. 1.
    Faderl S, Keating MJ, Do KA, Liang SY, Kantarjian HM, O’Brien S, et al. Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocyticleukemia (CLL). Leukemia. 2002;16(6):1045–52.CrossRefPubMedGoogle Scholar
  2. 2.
    Keshgegian AA, Johnston E, Cnaan A. Bcl-2 oncoprotein positivity and high MIB-1 (Ki-67) proliferative rate are independent predictive markers for recurrence in prostate carcinoma. Am J Clin Pathol. 1998;110(4):443–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Ofner D, Riehemann K, Maier H, et al. Immunohistochemically detectable bcl-2 expression in colorectal carcinoma: correlation with tumor stage and patient survival. Br J Cancer. 1995;72:981–98.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Silvestrini R, Benini E, Veneroni S, Daidone MG, et al. p53 and bcl-2 expression correlates with clinical outcome in a series of node-positive breast cancer patients. J Clin Oncol. 1996;14(5):1604–10.CrossRefPubMedGoogle Scholar
  5. 5.
    Seto M, Jaeger U, et al. Alternative promoter and exons, somatic mutation and deregulation of the Bcl-2 Ig fusion gene in lymphoma. EMBO J. 1988;7(1):123–31.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Young RL, Korsmeyer SJ. A negative regulatory element in the bcl-2 5′-untranslated region inhibits expression from an upstream promoter. Mol Cell Biol. 1993;13(6):3686–97.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bachmann HS, Heukamp LC, et al. Regulatory BCL2 promoter polymorphism (-938C>A) is associated with adverse outcome in patients with prostate carcinoma. Int J Cancer. 2011;129(10):2390–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Cingeetham A, Vuree S, Dunna NR, Gorre M, Nanchari SR, Edathara PM, Meka P et al. Influence of BCL2 -938C > A and BAX-248G > A promoter polymorphisms in the development of AML: case-control study from South India. Tumor Biol. 2015;36(10): 7967–76.Google Scholar
  9. 9.
    Li W, Qian C, et al. Association of BCL2-938C>A genetic polymorphism with glioma risk in Chinese Han population. Tumor Biol. 2014;35:2259–64.CrossRefGoogle Scholar
  10. 10.
    Lehnerdt GF, Franz P, Bankfalvi A, et al. The regulatory BCL2 promoter polymorphism (2938C>A) is associated with relapse and survival of patients with oropharyngeal squamous cell carcinoma. Ann Oncol. 2009;20:1094–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Nuckel H, Frey UH et al. Association of a novel regulatory polymorphism (_938C_A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia. Blood. 2007;109(1):290–7.Google Scholar
  12. 12.
    Bachmann HS, Otterbach F, Callies R, et al. The AA Genotype of the Regulatory BCL2 Promoter Polymorphism (-938C>A) Is Associated with a Favorable Outcome in Lymph Node-Negative Invasive Breast Cancer patients. Clin Cancer Res. 2007;13:5790–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Majid A, Tsoulakis O, Walewska R, et al. BCL2 expression in chronic lymphocytic leukemia: lack of association with the BCL2 938A>C promoter single nucleotide polymorphism. Blood. 2008;111(2):874–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Pikor LA, Enfield KS, Cameron H, Lam WL. DNA extraction from paraffin embedded material for genetic and epigenetic analyses. J Vis Exp. 2011;49:2763.Google Scholar
  15. 15.
    Klintman M, Bendahl PO, Grabau D, Lovgren K, Malmstrom P, Ferno M. The prognostic value of Ki67 is dependent on estrogen receptor status and histological grade in premenopausal patients with node-negative breast cancer. Mod Pathol. 2010;23(2):251–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Kim OH, Jo HY, Lee J, Yoon SK. The C1772T genetic polymorphism in human HIF-1α gene associates with expression of HIF-1α protein in breast cancer. Oncol. Rep. 2008;20(5):1181–7.Google Scholar
  17. 17.
    Meka PB, Cingeetham A, Nanchari SR, et al. HIF-1a (1772C>T) polymorphism as marker for breast cancer development. Tumor Biol. 2014;36:3215–20.CrossRefGoogle Scholar
  18. 18.
    Simoes-Wust AP, Schurpf T, Hall J, Stahel RA, Zangemeister-Wittke U. Bcl-2/bcl-xL bispecific antisense treatment sensitizes breast carcinoma cells to doxorubicin, paclitaxel and cyclophosphamide. Breast Cancer Res Treat. 2002;76(2):157–66.CrossRefPubMedGoogle Scholar
  19. 19.
    Pepper C, Hooper K, et al. Bcl-2 antisense oligonucleotides enhance the cytotoxicity of chlorambucil in B-cell chronic lymphocytic leukaemia cells. Leuk Lymphoma. 2001;42(3):491–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Phanni bhushann Meka
    • 1
  • Sarika Jarjapu
    • 1
  • Sandeep Kumar Vishwakarma
    • 2
  • Santhoshi Rani Nanchari
    • 1
  • Anuradha Cingeetham
    • 1
  • Sandhya Annamaneni
    • 1
  • Srinivasulu Mukta
    • 3
  • B. Triveni
    • 3
  • Vishnupriya Satti
    • 1
  1. 1.Department of GeneticsOsmania UniversityHyderabadIndia
  2. 2.Central Laboratory for Stem Cell Research & Translational Medicine, CLRDDeccan College of Medical SciencesHyderabadIndia
  3. 3.MNJ Institute of Oncology & Regional Cancer CentreHyderabadIndia

Personalised recommendations