Abstract
Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually1. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, θ=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.
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Acknowledgements
The authors thank all the family members who participated in this study. In addition, the assistance of physicians who referred patients to this study is gratefully acknowledged. The authors wish to thank K. Vaherto, M. Kuorilehto, R. Sankila, E. Pukkala and J. Viitanen for assistance in family collection in Finland. This work was supported by the National Institutes of Health (SPORE CA58236, CA72818 and NO1-HG-55389); The Fund for Research and Progress in Urology, The Johns Hopkins University; Academy of Finland; Reino Lahtikari and Sigrid Juselius Foundations; Finnish Cancer Society; Medical Research Fund of Tampere University Hospital; Swedish Cancer Society (Cancerfonden); Lion's Cancer Foundation, Department of Oncology, Umeå University; and CaPCURE. S.I. is supported by the GE Fund. D.F. is supported by the American Foundation for Urologic Disease.
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Xu, J., Meyers, D., Freije, D. et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. . Nat Genet 20, 175–179 (1998). https://doi.org/10.1038/2477
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DOI: https://doi.org/10.1038/2477
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