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

Huse K.a · Taudien S.a · Groth M.a, c · Rosenstiel P.d · Szafranski K.a · Hiller M.f · Hampe J.d · Junker K.b · Schubert J.b · Schreiber S.d · Birkenmeier G.c · Krawczak M.e · Platzer M.a
aGenome Analysis, Leibniz Institute for Age Research, Fritz Lipmann Institute and bDepartment of Urology, Friedrich Schiller University, Jena, cInstitute of Biochemistry, University of Leipzig, Leipzig, dInstitute for Clinical Molecular Biology and eInstitute of Medical Informatics and Statistics, Christian Albrechts University, Kiel, and fInstitute of Computer Science, Bioinformatics Group, Albert Ludwigs University Freiburg, Freiburg, Germany Tumor Biol 2008;29:83–92 (DOI:10.1159/000135688)

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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