Genomic scan of 254 hereditary prostate cancer families

Abstract

Hereditary prostate cancer (HPC) is a genetically heterogeneous disease, complicating efforts to map and clone susceptibility loci. We have used stratification of a large dataset of 254 HPC families in an effort to improve power to detect HPC loci and to understand what types of family features may improve locus identification. The strongest result is that of a dominant locus at 6p22.3 (heterogeneity LOD (HLOD) = 2.51), the evidence for which is increased by consideration of the age of PC onset (HLOD = 3.43 in 214 families with median age-of-onset 56-72 years) and co-occurrence of primary brain cancer (HLOD = 2.34 in 21 families) in the families. Additional regions for which we observe modest evidence for linkage include chromosome 7q and 17p. Only weak evidence of several previously implicated HPC regions is detected. These analyses support the existence of multiple HPC loci, whose presence may be best identified by analyses of large, including pooled, datasets which consider locus heterogeneity.

Identification of a prostate cancer susceptibility locus on chromosome 7q11–21 in Jewish families

“…Janer et al (47) observed a peak LOD score at marker D7S2212 on 7q21 by using a recessive parametric model, with an HLOD of 2. 25 (LOD ϭ 1.55).…”

“…In late 2003, eight additional genomewide scans for prostate cancer susceptibility loci were reported, including our own studies of 254 Prostate Cancer Genetic Research Study (PROGRESS) and 188 Johns Hopkins University (JHU) families (47,48). The aggregate results are summarized in a review by Easton et al (49).…”

Genetic Susceptibility to Aggressive Prostate Cancer

“…Slager and colleagues (39), using Gleason grade as a quantitative trait, also found a suggestive linkage signal in this same region. Other groups reported linkage on chromosome 6, but at some distance from this locus (14,16).…”

“…33). In this study, we used clinical data from 784 affected men from 248 HPC families for whom a genomic screen had been previously done (16). Disease characteristics such as Gleason score, stage, and PSA were used to classify affected men into categories of clinically insignificant, moderate, or aggressive prostate cancer.…”

“…Efforts to identify susceptibility loci for hereditary prostate cancer (HPC) have been ongoing for several years with only limited success (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). At the heart of the problem is extreme locus heterogeneity and disease heterogeneity (26)(27)(28)(29)(30).…”