Genetic variants of the copy number polymorphic beta-defensin locus are associated with sporadic prostate cancer.
OBJECTIVE
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 beta-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.
Huse
Klaus
K
Genome Analysis, Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
Taudien
Stefan
S
Groth
Marco
M
Rosenstiel
Philip
P
Szafranski
Karol
K
Hiller
Michael
M
Hampe
Jochen
J
Junker
Kerstin
K
Schubert
Jorg
J
Schreiber
Stefan
S
Birkenmeier
Gerd
G
Krawczak
Michael
M
Platzer
Matthias
M
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D023083:beta-Defensins / Q000235:genetics*
D014408:Biomarkers, Tumor; C106641:DEFB4A protein, human; D023083:beta-Defensins