Linkage and association studies of prostate cancer susceptibility: Evidence for linkage at 8p22-23

Multiple lines of evidence have implicated the short arm of chromosome 8 as harboring genes important in prostate carcinogenesis. Although most of thi s evidence comes from the identification of frequent somatic alterations of 8p loci in prostate cancer cells (e.g., loss of heterozygosity), studies h ave also suggested a role for 8p genes in mediation of inherited susceptibi lity to prostate cancer. To further examine this latter possibility, we per formed linkage analyses, in 159 pedigrees affected by hereditary prostate c ancer (HPC), using 24 markers on the short arm of chromosome 8. In the comp lete set of families, evidence for prostate cancer linkage was found at 8p2 2-23, with a peak HLOD of 1.84 (P = .004), and an estimate of the proportio n of families linked (alpha) of 0.14, at D8S1130. In the 79 families with a verage age at diagnosis >65 years, an allele-sharing LOD score of 2.64 (P = .005) was observed, and six markers spanning a distance of 10 cM had LOD s cores >2.0. Interestingly, the small number of Ashkenazi Jewish pedigrees ( n = 11) analyzed in this study contributed disproportionately to this linka ge. Mutation screening in HPC probands and association analyses in case sub jects (a group that includes HPC probands and unrelated case subjects) and unaffected control subjects were carried out for the putative prostate canc er-susceptibility gene, PG1, previously localized to the 8p22-23 region. No statistical differences in the allele, genotype, or haplotype frequencies of the SNPs or other sequence variants in the PG1 gene were observed betwee n case and control subjects. However, case subjects demonstrated a trend to ward higher homozygous rates of less-frequent alleles in all three PG1 SNPs , and overtransmission of a PG1 variant to case subjects was observed. In s ummary, these results provide evidence for the existence of a prostate canc er-susceptibility gene at 8p22-23. Evaluation of the PG1 gene and other can didate genes in this area appears warranted.