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Germline BCL-2 sequence variants and inherited predisposition to prostate cancer

Prostate Cancer and Prostatic Diseases volume 9, pages 284–292 (2006)Cite this article

Abstract

Apoptosis is an essential physiological process that regulates cellular proliferation. Here, we explored the effect of DNA sequence variation within the BCL-2 gene on prostate cancer susceptibility in three clinical populations, consisting of 428 African Americans, 214 Jamaicans and 218 European Americans. We observed a 70% reduced risk for prostate cancer among the European Americans who had possessed two copies of a promoter variant −938C/A. Additionally, common BCL-2 haplotypes appeared to influence prostate cancer risk; however, studies in larger data sets are needed to confirm our findings. Our data suggest that inherited BCL-2 variants may be associated with a decrease in prostate cancer susceptibility.

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References

  1. American Cancer Society. Factors that influence cancer rates. Cancer Fact and Figures 2005 2005, 59–60.

  2. Glover Jr FE, Coffey DS, Douglas LL, Cadogan M, Russell H, Tulloch T et al. The epidemiology of prostate cancer in Jamaica. J Urol 1998; 159: 1984–1986.

    Article  Google Scholar 

  3. Tang DG, Porter AT . Target to apoptosis: a hopeful weapon for prostate cancer. Prostate 1997; 32: 284–293.

    Article  CAS  Google Scholar 

  4. Tsujimoto Y, Bashir MM, Givol I, Cossman J, Jaffe E, Croce CM . DNA rearrangements in human follicular lymphoma can involve the 5′ or the 3′ region of the bcl-2 gene. Proc Natl Acad Sci USA 1987; 84: 1329–1331.

    Article  CAS  Google Scholar 

  5. Tapia-Vieyra JV, Mas-Oliva J . Apoptosis and cell death channels in prostate cancer. Arch Med Res 2001; 32: 175–185.

    Article  CAS  Google Scholar 

  6. Oltvai ZN, Milliman CL, Korsmeyer SJ . Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74: 609–619.

    Article  CAS  Google Scholar 

  7. Wang K, Gross A, Waksman G, Korsmeyer SJ . Mutagenesis of the BH3 domain of BAX identifies residues critical for dimerization and killing. Mol Cell Biol 1998; 18: 6083–6089.

    Article  CAS  Google Scholar 

  8. Baliga BC, Kumar S . Role of Bcl-2 family of proteins in malignancy. Hematol Oncol 2002; 20: 63–74.

    Article  Google Scholar 

  9. Cory S, Adams JM . The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2002; 2: 647–656.

    Article  CAS  Google Scholar 

  10. Reed JC . Mechanisms of apoptosis. Am J Pathol 2000; 157: 1415–1430.

    Article  CAS  Google Scholar 

  11. Petros AM, Nettesheim DG, Wang Y, Olejniczak ET, Meadows RP, Mack J et al. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci 2000; 9: 2528–2534.

    Article  CAS  Google Scholar 

  12. Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M et al. Structure of Bcl-xL–Bak peptide complex: recognition between regulators of apoptosis. Science 1997; 275: 983–986.

    Article  CAS  Google Scholar 

  13. Bonkhoff H, Remberger K . Differentiation pathways and histogenetic aspects of normal and abnormal prostatic growth: a stem cell model. Prostate 1996; 28: 98–106.

    Article  CAS  Google Scholar 

  14. Johnson MI, Robinson MC, Marsh C, Robson CN, Neal DE, Hamdy FC . Expression of Bcl-2, Bax, and p53 in high-grade prostatic intraepithelial neoplasia and localized prostate cancer: relationship with apoptosis and proliferation. Prostate 1998; 37: 223–229.

    Article  CAS  Google Scholar 

  15. Kaur P, Kallakury BS, Sheehan CE, Fisher HA, Kaufman RP, Ross JS . Survivin and Bcl-2 expression in prostatic adenocarcinomas. Arch Pathol Lab Med 2004; 128: 39–43.

    PubMed  Google Scholar 

  16. Hering FL, Lipay MV, Lipay MA, Rodrigues PR, Nesralah LJ, Srougi M . Comparison of positivity frequency of bcl-2 expression in prostate adenocarcinoma with low and high Gleason score. Sao Paulo Med J 2001; 119: 138–141.

    Article  CAS  Google Scholar 

  17. Bonkhoff H, Fixemer T, Remberger K . Relation between Bcl-2, cell proliferation, and the androgen receptor status in prostate tissue and precursors of prostate cancer. Prostate 1998; 34: 251–258.

    Article  CAS  Google Scholar 

  18. Colombel M, Symmans F, Gil S, O'Toole KM, Chopin D, Benson M et al. Detection of the apoptosis-suppressing oncoprotein bc1-2 in hormone-refractory human prostate cancers. Am J Pathol 1993; 143: 390–400.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Lipponen P, Vesalainen S . Expression of the apoptosis suppressing protein bcl-2 in prostatic adenocarcinoma is related to tumor malignancy. Prostate 1997; 32: 9–15.

    Article  CAS  Google Scholar 

  20. McConkey DJ, Greene G, Pettaway CA . Apoptosis resistance increases with metastatic potential in cells of the human LNCaP prostate carcinoma line. Cancer Res 1996; 56: 5594–5599.

    CAS  PubMed  Google Scholar 

  21. Lang G, Gombert WM, Gould HJ . A transcriptional regulatory element in the coding sequence of the human Bcl-2 gene. Immunology 2005; 114: 25–36.

    Article  CAS  Google Scholar 

  22. Grabe N . AliBaba2: context specific identification of transcription factor binding sites. In Silico Biol 2002; 2: S1–S15.

    PubMed  Google Scholar 

  23. Kittles RA, Young D, Weinrich S, Hudson J, Argyropoulos G, Ukoli F et al. Extent of linkage disequilibrium between the androgen receptor gene CAG and GGC repeats in human populations: implications for the prostate cancer risk. Cancer Risk 2001; 109: 253–261.

    CAS  Google Scholar 

  24. Panguluri R, Chen W, Kittles R . SNP genotyping of candidate genes for complex diseases using pyrosequencing. Am Biotechnol Lab 2002; 20: 30–34.

    CAS  Google Scholar 

  25. Satten GA, Epstein MP . Comparison of prospective and retrospective methods for haplotype inference in case–control studies. Genet Epidemiol 2004; 27: 192–201.

    Article  Google Scholar 

  26. 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: 443–449.

    Article  CAS  Google Scholar 

  27. Sinicrope FA, Hart J, Michelassi F, Lee JJ . Prognostic value of bcl-2 oncoprotein expression in stage II colon carcinoma. Clin Cancer Res 1995; 1: 1103–1110.

    CAS  PubMed  Google Scholar 

  28. Anton RC, Brown RW, Younes M, Gondo MM, Stephenson MA, Cagle PT . Absence of prognostic significance of bcl-2 immunopositivity in non-small cell lung cancer: analysis of 427 cases. Hum Pathol 1997; 28: 1079–1082.

    Article  CAS  Google Scholar 

  29. aka-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: 259–264.

    Article  Google Scholar 

  30. Meterissian SH, Kontogiannea M, Al-Sowaidi M, Linjawi A, Halwani F, Jamison B et al. Bcl-2 is a useful prognostic marker in Dukes' B colon cancer. Ann Surg Oncol 2001; 8: 533–537.

    CAS  PubMed  Google Scholar 

  31. Nakamura T, Nomura S, Sakai T, Nariya S . Expression of bcl-2 oncoprotein in gastrointestinal and uterine carcinomas and their premalignant lesions. Hum Pathol 1997; 28: 309–315.

    Article  CAS  Google Scholar 

  32. Stattin P . Prognostic factors in prostate cancer. Scand J Urol Nephrol Suppl 1997; 185: 1–46.

    CAS  PubMed  Google Scholar 

  33. Lu QL, Abel P, Foster CS, Lalani EN . bcl-2: role in epithelial differentiation and oncogenesis. Hum Pathol 1996; 27: 102–110.

    Article  CAS  Google Scholar 

  34. McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT et al. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 1992; 52: 6940–6944.

    CAS  PubMed  Google Scholar 

  35. Kallakury BV, Figge J, Leibovich B, Hwang J, Rifkin M, Kaufman R et al. Increased bcl-2 protein levels in prostatic adenocarcinomas are not associated with rearrangements in the 2.8 kb major breakpoint region or with p53 protein accumulation. Mod Pathol 1996; 9: 41–47.

    CAS  PubMed  Google Scholar 

  36. Bauer JJ, Sesterhenn IA, Mostofi FK, McLeod DG, Srivastava S, Moul JW . Elevated levels of apoptosis regulator proteins p53 and bcl-2 are independent prognostic biomarkers in surgically treated clinically localized prostate cancer. J Urol 1996; 156: 1511–1516.

    Article  CAS  Google Scholar 

  37. Wilson BE, Mochon E, Boxer LM . Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis. Mol Cell Biol 1996; 16: 5546–5556.

    Article  CAS  Google Scholar 

  38. Heckman CA, Mehew JW, Boxer LM . NF-kappaB activates Bcl-2 expression in t(14;18) lymphoma cells. Oncogene 2002; 21: 3898–3908.

    Article  CAS  Google Scholar 

  39. Xie W, Wong YC, Tsao SW . Correlation of increased apoptosis and proliferation with development of prostatic intraepithelial neoplasia (PIN) in ventral prostate of the Noble rat. Prostate 2000; 44: 31–39.

    Article  CAS  Google Scholar 

  40. Kaklamanis L, Savage A, Mortensen N, Tsiotos P, Doussis-Anagnostopoulou I, Biddolph S et al. Early expression of bcl-2 protein in the adenoma–carcinoma sequence of colorectal neoplasia. J Pathol 1996; 179: 10–14.

    Article  CAS  Google Scholar 

  41. Ter B, Smedts F, Kuijpers J, Jeunink M, Trimbos B, Ramaekers F . BCL-2 immunoreactivity increases with severity of CIN: a study of normal cervical epithelia, CIN, and cervical carcinoma. J Pathol 1996; 179: 26–30.

    Article  Google Scholar 

  42. Royuela M, De Miguel MP, Bethencourt FR, Fraile B, Arenas MI, Paniagua R . IL-2, its receptors, and bcl-2 and bax genes in normal, hyperplastic and carcinomatous human prostates: immunohistochemical comparative analysis. Growth Factors 2000; 18: 135–146.

    Article  CAS  Google Scholar 

  43. Chi KN, Gleave ME . Antisense approaches in prostate cancer. Expert Opin Biol Ther 2004; 4: 927–936.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all the men who volunteered to participate in this genetic study. This work was supported by the NIH (1U54CA91431-01), the Department of Defense (DAMD17-00-1-0025 and DAMD 17-02-1-0067) and the Howard University Cancer Center.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Cancer Prevention and Control Program, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA

    L R Kidd & T M Templeton

  2. National Human Genome Center at Howard University, Washington, DC, USA

    A Coulibaly, W Chen, L O Long, T Mason, C Bonilla, F Akereyeni, C Ahaghotu & R A Kittles

  3. Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    C Bonilla & R A Kittles

  4. Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA

    V Freeman

  5. Department of Urology, Loyola University Stritch School of Medicine, Maywood, IL, USA

    V Freeman

  6. Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    W Isaacs

  7. Divison of Urology, Howard University Hospital, Washington, DC, USA

    C Ahaghotu & R A Kittles

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  1. L R Kidd
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Correspondence to R A Kittles.

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Kidd, L., Coulibaly, A., Templeton, T. et al. Germline BCL-2 sequence variants and inherited predisposition to prostate cancer. Prostate Cancer Prostatic Dis 9, 284–292 (2006). https://doi.org/10.1038/sj.pcan.4500884

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  • DOI: https://doi.org/10.1038/sj.pcan.4500884

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