Prostate cancer susceptibility locus HPC1 in Utah high-risk pedigrees

Abstract

A prostate cancer susceptibility locus (HPC1) at 1q24-25 has been identified. Subsequent analysis showed that the majority of the evidence for localization was provided by families with relatively young (< 65 years) average age at diagnosis. We examined evidence for linkage to this region in a set of 41 extended multi-case prostate cancer pedigrees containing 440 prostate cancer cases. Genotyping of five short tandem repeat markers in the region was performed on DNA from 1724 individuals, including 284 prostate cancer cases. In comparison with the families reported in the initial localization, the Utah pedigrees are generally much larger (average of 10.7 versus 5.1 cases) and have an older average age at diagnosis (69 versus 65 years). Two- and three-point linkage analyses were conducted using a previously reported model and provided replication for HPC1 (two-point: LOD = 1.73, P = 0.005 at D1S196; three-point: LOD = 2.06, P= 0.002 for the interval D1S196-D1S416). The youngest quartile (by median age at diagnosis) yielded a maximum LOD of 2.82, P = 0.0003 (at D1S215-D1S222), compared with a maximum LOD of 0.73, P = 0.07 for the oldest quartile pedigrees at the same locus. Further analysis with an age-dependent model, specifying higher sporadic rates for older cases, suggests that the linkage evidence may be lower than expected given the power of the resource due to a high sporadic rate in the large Utah pedigrees.