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Prostate cancer is a complex disease with a substantial genetic contribution involved in the disease risk. Several genomewide linkage studies conducted so far have demonstrated a strong heterogeneity of susceptibility. In order to assess candidate regions that are particularly relevant for the German population, we performed a genomewide linkage search on 139 prostate cancer families. A nonparametric method (Zlr scores), using GENEHUNTERPLUS, was applied at 500 markers (panel P1400, deCODE), with an average spacing of 7.25 cM. In the entire family collection, linkage was most evident at 8p22 (Zlr=2.47, P=0.0068), close to the previously identified susceptibility gene MSR1. Further local maxima with Zlr>2 (P<0.025) were observed at 1q, 5q and 15q. In a subgroup of 47 families, which matched the Johns Hopkins criteria of hereditary prostate cancer, suggestive linkage was found on 1p31 (Zlr=3.37, P=0.00038), a previously not described candidate region. The remaining 92 pedigrees, with no strong disease history, revealed a maximum Zlr=3.15 (P=0.00082) at 8q13, possibly indicating a gene with reduced penetrance or recessive inheritance. Our results suggest pronounced locus heterogeneity of prostate cancer susceptibility in Germany. In the present study population, the MSR1 gene could play a significant role. Other conspicuous loci, like 1p31 and 8q13, need further investigation in order to verify their relevance and to identify candidate genes.

It has been suggested that chromosome 7q32 contains genes that influence the progression of prostate cancer from latent to invasive disease. In an attempt to confirm this linkage to prostate cancer aggressiveness, 100 German prostate cancer families were genotyped using a panel of eight polymorphic markers on chromosome 7q. We used a multipoint allele sharing method based upon a likelihood ratio test implemented in GENEHUNTERPLUS v1.2 in order to calculate the nonparametric Z(lr) and the associated LOD scores. We applied the aggressiveness of prostate cancer given by the pathological tumour grade of each individual, and the mean age of onset of a family as covariates, and constructed two weighted models. The first (weight(0-1) model) puts weights on families with at least two cases of GIII prostate cancer. The second (weight(0-2) model) also adds weights to families with early and late onset cancer respectively. The unweighted analysis gave no evidence of linkage to chromosome 7q. The Z(lr) scores increased when including the covariates, to 2.60 (P=0.005) using the weight(0-1) and to 3.02 (P=0.001) using the weight(0-2) model for late onset prostate cancer. The associated LOD scores were respectively 1.47 (P=0.009) and 1.98 (P=0.002). The markers that gave most evidence for linkage were exactly in the range of the published prostate cancer aggressiveness region. Our results support a widespread relevance of this locus and suggest that aggressive and late onset prostate cancer is linked to chromosme 7q31-33 in the German population.

Alleles of the CAG and the GGC repeat in the first exon of the human androgen receptor (AR) gene have been shown to be associated with the risk of (advanced) prostate cancer. These studies had been carried out in the United States. We have analysed these polymorphisms in a French-German collection of 105 controls, 132 sporadic cases, and a sample of prostate cancer families comprising 85 affected and 46 not affected family members. The allele distributions were very similar in all four groups and chi square statistics on contingency tables did not detect any significant differences. The relative risk (odds ratio, OR) were calculated using logistic regression and did not reach significance despite sufficient numbers of patients and controls. Typical results were OR = 1.007; 95% Confidence Interval (CI) 0.97-1.1, P = 0.87 for CAG as continuous variable and OR = 1.2 (95% CI 0.7-2.0), P = 0.47 for CAG classes < 22 and > = 22 repeats. Similar results were obtained for subgroups defined by age or Gleason score. We conclude that these polymorphisms can not be used as predictive parameters for prostate cancer in the French or German population.