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Early Age at Diagnosis in Families Providing Evidence of Linkage to the Hereditary Prostate Cancer Locus (HPC1) on Chromosome 1¹

James Buchanan Brady Urological Institute, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287-2101 [H. G., S. D. I., D. F., G. S. B., P. C. W., W. B. I.]; Department of Oncology, Umeå University, 901 85 Umeå, Sweden [H. G.]; Center for the Genetics of Asthma and Complex Diseases, University of Maryland, School of Medicine, Baltimore, Maryland 21201 [J. X., D. A. M.]; and National Human Genome Research Institute, NIH, Bethesda, Maryland 20892 [J. R. S., J. D. C., F. S. C., J. M. T.]

In a recent study of 91 families having at least three first degree relatives with prostate cancer, we reported the localization of a major susceptibility locus for prostate cancer (HPC1) to chromosome 1 [band q24; J. R. Smith et al., Science (Washington DC), 274: 1371–1373, 1996]. There was significant evidence for locus heterogeneity, with an estimate of 34% of the families being linked to this locus. In this report, we investigate the importance of age at diagnosis of prostate cancer and number of affected individuals within a family as variables in the linkage analysis of an expanded set of markers on 1q24. Under two different models for the prostate cancer locus, we find that the evidence for linkage to HPC1 is provided primarily by large (five or more members affected) families with an early average age at diagnosis. Specifically, for 40 North American families with an average age at diagnosis <65 years, the multipoint lod score is 3.96, whereas for 39 families with an older average age at diagnosis, this value is -0.84. Assuming heterogeneity, the proportion of families linked is 66% for the 14 families with the earliest average ages at diagnoses, but it decreases to 7% for the families with the latest ages at diagnoses. A similar age effect is observed in 12 Swedish pedigrees analyzed. To test the hypotheses generated by these analyses, we examined an additional group of 13 newly identified prostate cancer families. Overall, these families provided additional evidence for linkage to this region (nonparametric linkage Z = 1.91; P = 0.04 at marker D1S1660), contributed primarily by the families in this group with early age at diagnosis [nonparametric linkage Z = 2.50 (P = 0.01) at D1S422]. These results are consistent with the existence of a locus in this region that predisposes men to develop early-onset prostate cancer.

¹ This work was supported by USPHS Specialized Programs of Research Excellence Grant CA58236; by grants from The Fund for Research and Progress in Urology (The Johns Hopkins University), Swedish Cancer Society (Cancerfonden), the Lion's Cancer Foundation, Department of Oncology, and Umeå Universitet; and by a CaPCURE Award. D. F. is supported by a grant from the American Foundation for Urological Disease. S. D. I. is supported by a grant from General Electric.

² These authors contributed equally to this work.

³ To whom requests for reprints should be addressed, at Brady Urological Institute, Marburg 130b, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287-2101. Phone: (410) 955-2518; Fax: (410) 955-0833.

Received 7/22/97. Accepted 9/22/97.

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