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CC genotype of anti-apoptotic gene BCL-2 (−938 C/A) is an independent prognostic marker of unfavorable clinical outcome in patients with non-small-cell lung cancer

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Abstract

Background

B cell lymphoma 2 (BCL-2) gene is a well-known regulator of apoptosis and a key element in cancer development and progression. A regulatory (−938C>A, rs2279115) single-nucleotide polymorphism in the inhibitory P2 BCL-2 gene promoter generates significantly different BCL-2 promoter activities and has been associated with different clinical outcomes in various malignancies. The aim of the present study was to analyze the possible influence of the (−938C>A) SNP on the risk and survival of Indian patients suffering from NSCLC.

Materials and methods

A hospital-based case–control study of 155 age- and sex-matched patients diagnosed with NSCLC and 155 cancer-free controls was conducted and genotyped by performing PIRA–PCR to elucidate the putative association between clinical outcome and genotypes of BCL-2 (−938C>A, rs2279115). The association of the polymorphism with the survival of NSCLC patients was analyzed by Kaplan–Meier curves.

Results

In Indian NSCLC, patients increased risk of developing NSCLC was found to be associated with BCL-2 (−938) CC genotype, [OR 3.68 (1.92−6.79), RR 1.87 (1.35−2.57) and RD 31.03 (16.79−45.27) p 0.00006 for CC and OR 2.08 (1.18−3.66), RR 1.36 (1.08−1.71) and RD 17.74 (4.68−30.81) p 0.01 for AC genotype]. Patients homozygous for C allele exhibited a significant poor overall survival compared with patients displaying AC + CC or AC or AA genotype [median survival (months) 8 vs. 11 vs. 14 vs. 35.5 (p < 0.0001)]. In addition, significant associations were observed between TNM stage, histological type, distant metastases status, family history of any cancer, gender and age group of NSCLC patients with BCL-2 (−938C>A) polymorphism.

Conclusion

Genetic polymorphism in the inhibitory P2 promoter region of anti-apoptotic BCL-2 genes contributes to the risk of developing non-small-cell lung cancer in Indian population. BCL-2 (−938CC) genotype was an independent adverse prognostic factor for patients with NSCLC.

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Abbreviations

BCL-2:

B cell lymphoma 2

SCC:

Squamous cell carcinoma

ADC:

Adenocarcinoma

NSCLC:

Non-small cell lung cancer

PIRA–PCR:

Primer-introduced restriction analysis–PCR

References

  1. American Cancer Society. 2012. Cancer facts and figures.

  2. World Health Organization. 2012. Cancer fact sheet. http://www.who.int/mediacentre/factsheets.

  3. Saintigny P, Burger JA. Recent advances in non small cell lung cancer biology and clinical management. Discov Med. 2012;71:287–97.

    Google Scholar 

  4. Dikshit R, Gupta PC, Ramasundarahettige C, Gajalakshmi V, Aleksandrowicz L, Badwe R, et al. Cancer mortality in India: a nationally representative survey. Lancet. 2012;379(9828):1807–16.

    Article  PubMed  Google Scholar 

  5. Shivapurkar N, Reddy J, Chaudhary PM, Gazdar AF. Apoptosis and lung cancer: a review. J Cell Biochem. 2003;88(5):885–98.

    Article  CAS  PubMed  Google Scholar 

  6. Hajra KM, Liu JR. Apoptosome dysfunction in human cancer. Apoptosis. 2004;9(6):691–704.

    Article  CAS  PubMed  Google Scholar 

  7. Liu W, Bulgaru A, Haigentz M, Stein CA, Perez-Soler R, Mani S. The BCL-2: family of protein ligands as cancer drugs: the next generation of therapeutics. Curr Med Chem Anticancer Agents. 2003;3(3):217–23.

    Article  CAS  PubMed  Google Scholar 

  8. An J, Chervin AS, Nie A, Ducoff HS, Huang Z. Overcoming the radioresistance of prostate cancer cells with a novel BCL-2 inhibitors. Oncogene. 2007;26(5):652–61.

    Article  CAS  PubMed  Google Scholar 

  9. Anai S, Goodison S, Shiverick K, Hirao Y, Brown BD, Rosser CJ. Knock-down of BCL-2 by antisense oligodeoxynucleotides induces radiosensitization and inhibition of angiogenesis of human PC-3 Prostate tumor xenografts. Mol Cancer Ther. 2007;6(1):101–11.

    Article  CAS  PubMed  Google Scholar 

  10. Oliver L, Mahe B, Gree R, Vallete FM, Juin P. HA14-1, a small molecule inhibitor of Bcl-2, bypass chemoresistance in leukaemia cells. Leuk Res. 2007;31(6):859–63.

    Article  CAS  PubMed  Google Scholar 

  11. Nuckel H, Frey UH, Bau M, Sellmann L, Stanelle J, Durig J, et al. Association of a novel regulatory polymorphism (−938C>A) in the BCL-2 gene promoter with disease progression and survival in chronic lymphocytic leukemia. Blood. 2007;109(1):290–7.

    Article  PubMed  Google Scholar 

  12. Bachmann HS, Heukamp LC, Schmitz KJ, Hilburn CF, Kahl P, Buettner R, et al. Regulatory BCL-2 promoter polymorphism (−938C>A) is associated with adverse outcome in patients with prostate carcinoma. Int J Cancer. 2011;129(10):2390–9.

    Article  CAS  PubMed  Google Scholar 

  13. Stackhouse GB, Sesterhenn IA, Bauer JJ, Mostofi FK, Connelly RR, Srivastava SK, et al. p53 and BCL-2 immunohistochemistry in pretreatment prostate needle biopsies to predict recurrence of prostate cancer after radical prostatectomy. J Urol. 1999;162(6):2040–5.

    Article  CAS  PubMed  Google Scholar 

  14. 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 lymphocytic leukemia (CLL). Leukemia. 2002;16(6):1045–52.

    Article  CAS  PubMed  Google Scholar 

  15. Bilim V, Tomita Y, Kawasaki T, Katagiri A, Imai T, Takeda M, et al. Prognostic value of BCL-2 and p53 expression in urinary tract transition cell cancer. J Natl Cancer Inst. 1996;88(10):686–8.

    Article  CAS  PubMed  Google Scholar 

  16. Bachmann HS, Otterbach F, Callies R, Nuckel H, Bau M, Schmid KW, et al. The AA genotype of the regulatory BCL-2 promoter polymorphism (−938C>A) is associated with a favorable outcome in lymph node negative invasive breast cancer patients. Clin Cancer Res. 2007;13(19):5790–7.

    Article  CAS  PubMed  Google Scholar 

  17. Lehnerdt GF, Franz P, Bankfalvi A, Grehl S, Kelava A, Nuckel H, et al. The regulatory BCL-2 promoter polymorphism (−938C>A) is associated with relapse and survival of patients with oropharyngeal squamous cell carcinoma. Ann Oncol. 2009;20(6):1094–9.

    Article  CAS  PubMed  Google Scholar 

  18. Hirata H, Hinoda Y, Nakajima K, Kikuno N, Suehiro Y, Tabatabai ZL, et al. The BCL-2 −938CC genotype has poor prognosis and lower survival in renal cancer. J Urol. 2009;182(2):721–7.

    Article  CAS  PubMed  Google Scholar 

  19. Martin B, Paesmans M, Berghmans T, Branle F, Ghisdal L, Mascaux C, et al. Role of Bcl-2 as a prognostic factor for survival in lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer. 2003;89(1):55–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Hu Z, Li C, Chen K, Wang LE, Sturgis EM, Spitz MR, et al. Single nucleotide polymorphisms in selected apoptotic genes and BPDE-induced apoptotic capacity in apparently normal primary lymphocytes: a genotype–phenotype correlation analysis. J Cancer Epidemiol. 2008;2008:147905.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Chen K, Hu Z, Wang LE, Sturgis EM, El-Naggar AK, Zhang W, et al. Single-nucleotide polymorphisms at the TP53-binding or responsive promoter regions of BAX and BCL-2 genes and risk of squamous cell carcinoma of the head and neck. Carcinogenesis. 2007;28(9):2008–12.

    Article  CAS  PubMed  Google Scholar 

  22. Liu Z, Sun R, Lu W, Dang C, Song Y, Wang C. The −938A/A genotype of BCL-2 gene is associated with esophageal cancer. Med Oncol. 2012;29(4):2677–83.

    Article  CAS  PubMed  Google Scholar 

  23. Laudanski J, Chyczewski L, Niklinska WE, Kretowska M, Furman M, Sawicki B, et al. Expression of bcl-2 protein in non-small cell lung cancer: correlation with clinicopathology and patient survival. Neoplasma. 1999;46(1):25–30.

    CAS  PubMed  Google Scholar 

  24. Yoshihito S, Shigekazu H, Yutaka T, Takeshi N. Bcl-2 protein expression correlates with better prognosis in patients with advanced non-small cell lung cancer. Anticancer Res. 2004;24(3b):1925–8.

    Google Scholar 

  25. Ohsaki Y, Toyoshima E, Fujiuchi S, Matsui H, Hirata S, Miyokawa N, et al. Bcl-2 and p53 protein expression in non-small cell lung cancers: correlation with survival time. Clin Cancer Res. 1996;2(5):915–20.

    CAS  PubMed  Google Scholar 

  26. Dosaka-Akita H, Katabami M, Hommura H, Fujioka Y, Katoh H, Kawakami Y. Bcl-2 expression in non-small cell lung cancers: higher frequency of expression in squamous cell carcinomas with earlier pT status. Oncology. 1999;56(3):259–64.

    Article  CAS  PubMed  Google Scholar 

  27. Cory S, Adams JM. The BCL-2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002;2(9):647–56.

    Article  CAS  PubMed  Google Scholar 

  28. Zinkel S, Gross A, Yang E. BCL-2 family in DNA damage and cell cycle control. Cell Death Differ. 2006;13(8):1351–9.

    Article  CAS  PubMed  Google Scholar 

  29. Hanson CJ, Bootman MD, Distelhorst CW, Maraldi T, Roderick HL. The cellular concentration of Bcl-2 determines its pro- or anti-apoptotic effect. Cell Calcium. 2008;44(3):243–58.

    Article  CAS  PubMed  Google Scholar 

  30. Linette GP, Li Y, Roth K, Korsmeyer SJ. Cross talk between cell death and cell cycle progression: BCL-2 regulates NFAT-mediated activation. Proc Natl Acad Sci USA. 1996;93(18):9545–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A, et al. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science. 1997;278(5345):1966–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank all the study subjects and Regional Cancer Center SKIMS, Srinagar and All India Institute of Medical Sciences, New Delhi, for assistance in recruiting the subjects.

Conflict of interest

None.

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Authors and Affiliations

  1. Cancer Genetics Lab, Department of Biochemistry, Maulana Azad Medical College and Associated hospitals, New Delhi, India

    J. Javid, R. Mir, M. Mirza, A. Imtiyaz, Y. Prasant, Z. Mariyam, P. C. Ray & A. Saxena

  2. Department of Radiotherapy and Oncology, All India Institute of Medical Sciences, New Delhi, India

    P. K. Julka

  3. Department of Medicine, All India Institute of Medical Sciences, New Delhi, India

    A. Mohan

  4. Department of Radiation Oncology, SKIMS, Srinagar, India

    M. Lone

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  1. J. Javid
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  2. R. Mir
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Correspondence to R. Mir.

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Javid, J., Mir, R., Mirza, M. et al. CC genotype of anti-apoptotic gene BCL-2 (−938 C/A) is an independent prognostic marker of unfavorable clinical outcome in patients with non-small-cell lung cancer. Clin Transl Oncol 17, 289–295 (2015). https://doi.org/10.1007/s12094-014-1226-2

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