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Clinical Characteristics of Prostate Cancer in an Analysis of Linkage to Four Putative Susceptibility Loci¹

Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, Washington 98195-7236 [E. L. G., J. L. S.]; Division of Medical Genetics, Department of Medicine, University of Washington Medical Center, Seattle, Washington 98195-7720 [E. L. G., M. D. B., G. P. J.]; Divisions of Public Health Sciences [J. L. S., S. K.] and Clinical Research [M. A. P., M. G., E. A. O.], Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024; and Institute for Systems Biology, Seattle, Washington 98105-6099 [M. J., L. H.]

Purpose: Hereditary prostate cancer is an etiologically heterogeneous disease with six susceptibility loci mapped to date. We aimed to describe a collection of high-risk prostate cancer families and assess linkage to multiple markers at four loci: HPC1 (1q24–25), PCaP (1q42.2–43), HPCX (Xq27–28), and CAPB (1p36).

Experimental Design: Medical record data on 505 affected men in 149 multiply-affected prostate cancer families were reviewed, and correlations of clinical traits within each family were calculated. Logarithm of odds (LOD) score and nonparametric (NPL) linkage analyses were performed; white families were stratified by age of diagnosis, grade and stage of disease, and evidence of linkage to the other loci to increase genetic homogeneity.

Results: Age at diagnosis was the most correlated clinical trait within families. A maximum NPL score of 2.61 (P = 0.007) appeared to confirm HPC1 linkage for families that had a prevalence of high-grade or advanced-stage prostate cancer and which were not likely to be linked to PCaP, HPCX, or CAPB. Because the NPL scores improved when families more likely to be linked to the other loci were excluded, HPC1 may act independently of the other loci. The relationship of HPC1 and aggressive disease was strongest in families with median age at diagnosis 65 years (NPL, 3.48; P = 0.0008).

Conclusions: The current results suggest that HPC1 linkage may be most common among families with more severe prostate cancer. Stratification by clinical characteristics may be a useful tool in prostate cancer linkage analyses and may increase our understanding of hereditary prostate cancer.

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