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Vol. 29, No. 2, 2008
Issue release date: July 2008

Genetic Variants of the Copy Number Polymorphic β-Defensin Locus Are Associated with Sporadic Prostate Cancer

Huse K. · Taudien S. · Groth M. · Rosenstiel P. · Szafranski K. · Hiller M. · Hampe J. · Junker K. · Schubert J. · Schreiber S. · Birkenmeier G. · Krawczak M. · Platzer M.
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Abstract

Background/Aims: Prostate cancer represents the cancer with the highest worldwide prevalence in men. Chromosome 8p23 has shown suggestive genetic linkage to early-onset familial prostate cancer and is frequently deleted in cancer cells of the urogenital tract. Within this locus some β-defensin genes (among them DEFB4, DEFB103, DEFB104) are localized, which are arranged in a gene cluster shown to exhibit an extensive copy number variation in the population. This structural variation considerably hampers genetic studies. In a new approach considering both sequence as well as copy number variations we aimed to compare the defensin locus at 8p23 in prostate cancer patients and controls. Methods: We apply PCR/cloning-based haplotyping and high-throughput copy number determination methods which allow assessment of both individual haplotypes and gene copy numbers not accessible to conventional SNP-based genotyping. Results: We demonstrate association of four common DEFB104 haplotypes with the risk of prostate cancer in two independent patient cohorts. Moreover, we show that high copy numbers (>9) of the defensin gene cluster are significantly underrepresented in both patient samples. Conclusions: Our findings imply a role of the antibacterial defensins in prostate cancerogenesis qualifying distinct gene variants and copy numbers as potential tumor markers.



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References

  1. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ: Cancer statistics, 2005. CA Cancer J Clin 2005;55:10–30.
  2. Xu J, Zheng SL, Hawkins GA, Faith DA, Kelly B, Isaacs SD, Wiley KE, Chang B, Ewing CM, Bujnovszky P, Carpten JD, Bleecker ER, Walsh PC, Trent JM, Meyers DA, Isaacs WB: Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22-23. Am J Hum Genet 2001;69:341–350.
  3. Wiklund F, Jonsson BA, Goransson I, Bergh A, Gronberg H: Linkage analysis of prostate cancer susceptibility: confirmation of linkage at 8p22-23. Hum Genet 2003;112:414–418.
  4. Chang BL, Liu W, Sun J, Dimitrov L, Li T, Turner AR, Zheng SL, Isaacs WB, Xu J: Integration of somatic deletion analysis of prostate cancers and germline linkage analysis of prostate cancer families reveals two small consensus regions for prostate cancer genes at 8p. Cancer Res 2007;67:4098–4103.
  5. Taudien S, Galgoczy P, Huse K, Reichwald K, Schilhabel M, Szafranski K, Shimizu A, Asakawa S, Frankish A, Loncarevic IF, Shimizu N, Siddiqui R, Platzer M: Polymorphic segmental duplications at 8p23.1 challenge the determination of individual defensin gene repertoires and the assembly of a contiguous human reference sequence. BMC Genomics 2004;5:92.
  6. Ganz T: Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 2003;3:710–720.
  7. Oppenheim JJ, Biragyn A, Kwak LW, Yang D: Roles of antimicrobial peptides such as defensins in innate and adaptive immunity. Ann Rheum Dis 2003;62(suppl 2):ii17–ii21.
  8. Quinones-Mateu ME, Lederman MM, Feng Z, Chakraborty B, Weber J, Rangel HR, Marotta ML, Mirza M, Jiang B, Kiser P, Medvik K, Sieg SF, Weinberg A: Human epithelial beta-defensins 2 and 3 inhibit HIV-1 replication. Aids 2003;17:F39–F48.
  9. Zhang L, Yu W, He T, Yu J, Caffrey RE, Dalmasso EA, Fu S, Pham T, Mei J, Ho JJ, Zhang W, Lopez P, Ho DD: Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1 activity of CD8 antiviral factor. Science 2002;298:995–1000.
  10. Fahlgren A, Hammarstrom S, Danielsson A, Hammarstrom ML: Beta-defensin-3 and -4 in intestinal epithelial cells display increased mRNA expression in ulcerative colitis. Clin Exp Immunol 2004;137:379–385.
  11. Fellermann K, Stange DE, Schaeffeler E, Schmalzl H, Wehkamp J, Bevins CL, Reinisch W, Teml A, Schwab M, Lichter P, Radlwimmer B, Stange EF: A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. Am J Hum Genet 2006;79:439–448.
  12. Hollox EJ, Huffmeier U, Zeeuwen PL, Palla R, Lascorz J, Rodijk-Olthuis D, van de Kerkhof PC, Traupe H, de Jongh G, den Heijer M, Reis A, Armour JA, Schalkwijk J: Psoriasis is associated with increased beta-defensin genomic copy number. Nat Genet 2008;40:23–25.
  13. Armour JA, Palla R, Zeeuwen PL, den Heijer M, Schalkwijk J, Hollox EJ: Accurate, high-throughput typing of copy number variation using paralogue ratios from dispersed repeats. Nucleic Acids Res 2007;35:e19.
  14. Hollox EJ, Armour JA, Barber JC: Extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster. Am J Hum Genet 2003;73:591–600.
  15. Linzmeier RM, Ganz T: Human defensin gene copy number polymorphisms: comprehensive analysis of independent variation in alpha- and beta-defensin regions at 8p22-p23. Genomics 2005;86:423–430.
  16. Karin M, Lawrence T, Nizet V: Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 2006;124:823–835.
  17. Lu H, Ouyang W, Huang C: Inflammation, a key event in cancer development. Mol Cancer Res 2006;4:221–233.
  18. Conejo-Garcia JR, Benencia F, Courreges MC, Kang E, Mohamed-Hadley A, Buckanovich RJ, Holtz DO, Jenkins A, Na H, Zhang L, Wagner DS, Katsaros D, Caroll R, Coukos G: Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med 2004;10:950–958.
  19. Candille SI, Kaelin CB, Cattanach BM, Yu B, Thompson DA, Nix MA, Kerns JA, Schmutz SM, Millhauser GL, Barsh GS: A beta-defensin mutation causes black coat color in domestic dogs. Science 2007;318:1418–1423.
  20. Donald CD, Sun CQ, Lim SD, Macoska J, Cohen C, Amin MB, Young AN, Ganz TA, Marshall FF, Petros JA: Cancer-specific loss of beta-defensin 1 in renal and prostatic carcinomas. Lab Invest 2003;83:501–505.
  21. Schullerus D, von Knobloch R, Chudek J, Herbers J, Kovacs G: Microsatellite analysis reveals deletion of a large region at chromosome 8p in conventional renal cell carcinoma. Int J Cancer 1999;80:22–24.
  22. Young AN, de Oliveira Salles PG, Lim SD, Cohen C, Petros JA, Marshall FF, Neish AS, Amin MB: Beta defensin-1, parvalbumin, and vimentin: a panel of diagnostic immunohistochemical markers for renal tumors derived from gene expression profiling studies using cDNA microarrays. Am J Surg Pathol 2003;27:199–205.
  23. Wu SQ, Hafez GR, Zhang J, Newton M, Chen A, Lange J, Wilding G: Identification of the prostate cancer micro-foci with chromosome 8p deletion at the tumor interface area by histopathological-FISH parallel examination. Int J Oncol 2001;19:1143–1147.
  24. Xu J, Zheng SL, Komiya A, Mychaleckyj JC, Isaacs SD, Chang B, Turner AR, Ewing CM, Wiley KE, Hawkins GA, Bleecker ER, Walsh PC, Meyers DA, Isaacs WB: Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Am J Hum Genet 2003;72:208–212.
  25. Groth M, Huse K, Reichwald K, Taudien S, Hampe J, Rosenstiel P, Birkenmeier G, Schreiber S, Platzer M: Method for preparing single-stranded DNA templates for Pyrosequencing using vector ligation and universal biotinylated primers. Anal Biochem 2006;356:194–201.
  26. Mars WM, Patmasiriwat P, Maity T, Huff V, Weil MM, Saunders GF: Inheritance of unequal numbers of the genes encoding the human neutrophil defensins HP-1 and HP-3. J Biol Chem 1995;270:30371–30376.
  27. Deutsch S, Choudhury U, Merla G, Howald C, Sylvan A, Antonarakis SE: Detection of aneuploidies by paralogous sequence quantification. J Med Genet 2004;41:908–915.
  28. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG: Inflammation in prostate carcinogenesis. Nat Rev Cancer 2007;7:256–269.
  29. Bonfield JK, Smith K, Staden R: A new DNA sequence assembly program. Nucleic Acids Res 1995;23:4992–4999.
  30. Fredman D, White SJ, Potter S, Eichler EE, Den Dunnen JT, Brookes AJ: Complex SNP-related sequence variation in segmental genome duplications. Nat Genet 2004;36:861–866.
  31. Andersson SO, Baron J, Bergstrom R, Lindgren C, Wolk A, Adami HO: Lifestyle factors and prostate cancer risk: a case-control study in Sweden. Cancer Epidemiol Biomarkers Prev 1996;5:509–513.
  32. Rosenblatt KA, Wicklund KG, Stanford JL: Sexual factors and the risk of prostate cancer. Am J Epidemiol 2001;153:1152–1158.
  33. Hochreiter WW, Duncan JL, Schaeffer AJ: Evaluation of the bacterial flora of the prostate using a 16S rRNA gene based polymerase chain reaction. J Urol 2000;163:127–130.
  34. Zheng SL, Augustsson-Balter K, Chang B, Hedelin M, Li L, Adami HO, Bensen J, Li G, Johnasson JE, Turner AR, Adams TS, Meyers DA, Isaacs WB, Xu J, Gronberg H: Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the Cancer Prostate in Sweden Study. Cancer Res 2004;64:2918–2922.
  35. Alexeyev O, Bergh J, Marklund I, Thellenberg-Karlsson C, Wiklund F, Gronberg H, Bergh A, Elgh F: Association between the presence of bacterial 16S RNA in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (Sweden). Cancer Causes Control 2006;17:1127–1133.
  36. Oudes AJ, Campbell DS, Sorensen CM, Walashek LS, True LD, Liu AY: Transcriptomes of human prostate cells. BMC Genomics 2006;7:92.
  37. Bailey JA, Eichler EE: Primate segmental duplications: crucibles of evolution, diversity and disease. Nat Rev Genet 2006;7:552–564.
  38. Freeman JL, Perry GH, Feuk L, Redon R, McCarroll SA, Altshuler DM, Aburatani H, Jones KW, Tyler-Smith C, Hurles ME, Carter NP, Scherer SW, Lee C: Copy number variation: new insights in genome diversity. Genome Res 2006;16:949–961.
  39. Lupski JR: Genome structural variation and sporadic disease traits. Nat Genet 2006;38:974–976.
  40. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, Gonzalez JR, Gratacos M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME: Global variation in copy number in the human genome. Nature 2006;444:444–454.
  41. Groth M, Szafranski K, Taudien S, Huse K, Mueller O, Rosenstiel P, Nygren AOH, Schreiber S, Birkenmeier G, Platzer M: High-resolution mapping of the 8p23.1 beta-defensin cluster reveals strictly concordant copy number variation of all genes. Hum Mutat, 2008 May 9. Epub ahead of print.
  42. Bernstein CN, Blanchard JF, Kliewer E, Wajda A: Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001;91:854–862.
  43. Aitman TJ, Dong R, Vyse TJ, Norsworthy PJ, Johnson MD, Smith J, Mangion J, Roberton-Lowe C, Marshall AJ, Petretto E, Hodges MD, Bhangal G, Patel SG, Sheehan-Rooney K, Duda M, Cook PR, Evans DJ, Domin J, Flint J, Boyle JJ, Pusey CD, Cook HT: Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 2006;439:851–855.
  44. Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G, Nibbs RJ, Freedman BI, Quinones MP, Bamshad MJ, Murthy KK, Rovin BH, Bradley W, Clark RA, Anderson SA, O’Connell RJ, Agan BK, Ahuja SS, Bologna R, Sen L, Dolan MJ, Ahuja SK: The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 2005;307:1434–1440.


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