Prostate Cancer, Hereditary, 8

For a general discussion of hereditary prostate cancer, see 176807.

Berthon et al. (1998) performed a linkage study using a set of European families (French and German) with 3 or more prostate cancer patients per family. They concluded that there is a prostate cancer susceptibility locus on 1q42.2-q43, significantly distant from HPC1 (601518) on 1q24-q25 (Smith et al., 1996). The primary localization was confirmed with several markers by use of 3 different genetic models. They obtained a maximum 2-point lod score of 2.7 with marker D1S2785. Multipoint parametric and nonparametric linkage (NPL) analysis yielded maximum hlod and NPL scores of 2.2 and 3.1, respectively, with an associated P value of 0.001. Homogeneity analysis with multipoint lod scores gave an estimate of the proportion of families with linkage to the 1q42.2-q43 locus of 50%, with a likelihood ratio of 157/1 in favor of heterogeneity. Furthermore, 9 of the 47 families with early-onset prostate cancer (at an age less than 60 years) gave multipoint lod and NPL scores of 3.31 and 3.32, respectively, with P = 0.001.

Gibbs et al. (1999) analyzed 152 families with prostate cancer for linkage to markers spanning a 20-cM region of 1q42.2-q43. No significant evidence for linkage was found, by use of both parametric and nonparametric tests, in the total data set, which included 522 genotyped affected men. Rejection of linkage may reflect locus heterogeneity or the confounding effects of sporadic disease in older-onset cases; therefore, the pedigrees were stratified into more homogeneous subsets based on mean age at diagnosis of prostate cancer and number of affected men. Analyses of these subsets also detected no significant evidence for linkage, although lod scores were positive at higher recombination fractions, which is consistent with the presence of a small proportion of families with linkage. The most suggestive evidence of linkage was in families with at least 5 affected men. If heterogeneity is assumed, an estimated 4 to 9% of these 152 families may show linkage in this region.

Cancel-Tassin et al. (2001) examined evidence for linkage to the PCAP locus in 64 (37 previously reported French, 24 newly identified French, 2 Spanish and 1 Italian) families with an average number of affected individuals of 3.75 and an average age at diagnosis of 66.4 years. Using both parametric and nonparametric linkage methods, results in favor of linkage were observed with a maximum multipoint NPL score of 2.86 at D1S2785 and a maximum hlod score of 2.65 between markers D1S321 and D1S2842. Homogeneity analysis indicated that up to 50% of the families were linked to this locus. A subset of 25 families with mean age at diagnosis under 66 years of age contributed significantly to the evidence of linkage with a maximum multipoint NPL score of 2.03 at D1S2842. These results suggested that PCAP is the most frequent known locus predisposing to hereditary prostate cancer in southern and western Europe.