Prostate cancer and genetic susceptibility: A genome scan incorporating disease aggressiveness

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Abstract
BACKGROUND Prostate cancer is a heterogeneous disease, both genetically and phenotypically. Linkage studies attempting to map genes for hereditary prostate cancer (HPC) have proved challenging, and one potential problem contributing to this challenge is the variability in disease phenotypes. METHODS We collected clinical data on 784 affected men with prostate cancer from 248 HPC families for whom a genomic screen was performed. Disease characteristics (i.e., Gleason score, stage, prostate-specific antigen (PSA)) were used to classify affected men into categories of clinically insignificant, moderate, or aggressive prostate cancer. To potentially enrich for a genetic etiology, we restricted linkage analyses to only men with aggressive disease, although we used genotype information from all family members; linkage analyses used both dominant and recessive models. In addition, subset analyses considered age at diagnosis, number of affected men per family and other stratifications to try to increase genetic homogeneity. RESULTS Several regions of interest (heterogeneity LOD score, HLOD > 1.0) were identified in families (n = 123) with ≥2 affecteds with aggressive prostate cancer. “Suggestive” linkage was observed at chromosome 22q11.1 (Dominant model HLOD = 2.18) and the result was stronger (Dominant HLOD = 2.75) in families with evidence of male-to-male transmission. A second region at 22q12.3-q13.1 was also highlighted (Recessive model HLOD = 1.90) among men with aggressive disease, as was a region on chromosome 18. CONCLUSIONS These analyses suggest that using clinically defined phenotypes may be a useful approach for simplifying the locus heterogeneity problems that confound the search for prostate cancer susceptibility genes.