Abstract
Several genetic predisposition loci for prostate cancer have been identified through linkage analysis, and it is now generally recognized that no single gene is responsible for more than a small proportion of prostate cancers. However, published confirmations of these loci have been few, and failures to confirm have been frequent. The genetic etiology of prostate cancer is clearly complex and includes significant genetic heterogeneity, phenocopies, and reduced penetrance. Powerful analyses that involve robust statistics and methods to reduce genetic heterogeneity are therefore necessary. We have performed linkage analysis on 143 Utah pedigrees for the previously published Xq27-28 (HPCX) prostate cancer susceptibility locus. We employed a robust multipoint statistic (TLOD) and a novel splitting algorithm to reduce intra-familial heterogeneity by iteratively removing the top generation from the large Utah pedigrees. In a dataset containing pedigrees having no more than five generations, we observed a multipoint TLOD of 2.74 (P=0.0002), which is statistically significant after correction for multiple testing. For both the full-structure pedigrees (up to seven generations) and the smaller sub-pedigrees, the linkage evidence was much reduced. This study thus represents the first significant confirmation of HPCX (Xq27-28) and argues for the continued utility of large pedigrees in linkage analyses for complex diseases.
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Acknowledgements
We thank two anonymous reviewers for their extremely helpful comments. Special thanks go to Marguerite Jost and Lewis Ershler (study coordinators), Kim Nguyen (laboratory specialist), and the many study participants without whom this research could not have progressed. Data collection for this publication was supported by NIH National Cancer Institute grant R01 CA90752 (to L.A. Cannon Albright) and a subcontract from Johns Hopkins University with funds provided by grant R01 CA89600 from the NIH National Cancer Institute (to L.A. Cannon Albright). Genotyping was provided by Myriad Genetics. Data collection was assisted by the Utah Cancer Registry supported by National Institutes of Health contracts NO1-PC-67000 and NO1-PC-35141, with additional support from the Utah Department of Health and the University of Utah. Partial support for all datasets within the Utah Population Database was provided by the University of Utah Huntsman Cancer Institute. This investigation was also supported by Public Health Services research grant number M01-RR00064 from the National Center for Research Resources.
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Farnham, J.M., Camp, N.J., Swensen, J. et al. Confirmation of the HPCX prostate cancer predisposition locus in large Utah prostate cancer pedigrees. Hum Genet 116, 179–185 (2005). https://doi.org/10.1007/s00439-004-1220-9
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DOI: https://doi.org/10.1007/s00439-004-1220-9