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Clinical and Translational Oncology
Published in: Clinical and Translational Oncology 4/2015

01-04-2015 | Research Article

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

Authors: J. Javid, R. Mir, M. Mirza, A. Imtiyaz, Y. Prasant, Z. Mariyam, P. K. Julka, A. Mohan, M. Lone, P. C. Ray, A. Saxena

Published in: Clinical and Translational Oncology | Issue 4/2015

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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.
Literature
1.
American Cancer Society. 2012. Cancer facts and figures.
2.
3.
Saintigny P, Burger JA. Recent advances in non small cell lung cancer biology and clinical management. Discov Med. 2012;71:287–97.
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.CrossRefPubMed
5.
Shivapurkar N, Reddy J, Chaudhary PM, Gazdar AF. Apoptosis and lung cancer: a review. J Cell Biochem. 2003;88(5):885–98.CrossRefPubMed
6.
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.PubMed
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.
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.PubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedCentralPubMed
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.CrossRefPubMed
Metadata
Title
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
Authors
J. Javid
R. Mir
M. Mirza
A. Imtiyaz
Y. Prasant
Z. Mariyam
P. K. Julka
A. Mohan
M. Lone
P. C. Ray
A. Saxena
Publication date
01-04-2015
Publisher
Springer Milan
Published in
Clinical and Translational Oncology / Issue 4/2015
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-014-1226-2

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