8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer

William D. Dupont, Joan P. Breyer, Walton Plummer (), Sam S. Chang, Michael S. Cookson, Joseph A. Smith, Elizabeth E. Blue, Michael J. Bamshad and Jeffrey R. Smith ()
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William D. Dupont: Vanderbilt University Medical Center
Joan P. Breyer: Vanderbilt University Medical Center
Sam S. Chang: Vanderbilt University Medical Center
Michael S. Cookson: University of Oklahoma Health Sciences Center
Joseph A. Smith: Vanderbilt University Medical Center
Elizabeth E. Blue: University of Washington, HSB H132
Michael J. Bamshad: University of Washington, HSB RR349
Jeffrey R. Smith: Vanderbilt University Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract The 8q24 genomic locus is tied to the origin of numerous cancers. We investigate its contribution to hereditary prostate cancer (HPC) in independent study populations of the Nashville Familial Prostate Cancer Study and International Consortium for Prostate Cancer Genetics (combined: 2,836 HPC cases, 2,206 controls of European ancestry). Here we report 433 variants concordantly associated with HPC in both study populations, accounting for 9% of heritability and modifying age of diagnosis as well as aggressiveness; 183 reach genome-wide significance. The variants comprehensively distinguish independent risk-altering haplotypes overlapping the 648 kb locus (three protective, and four risk (peak odds ratios: 1.5, 4, 5, and 22)). Sequence of the near-Mendelian haplotype reveals eleven causal mutation candidates. We introduce a linkage disequilibrium-based algorithm discerning eight independent sentinel variants, carrying considerable risk prediction ability (AUC = 0.625) for a single locus. These findings elucidate 8q24 locus structure and correlates for clinical prediction of prostate cancer risk.

Date: 2020
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DOI: 10.1038/s41467-020-15122-1

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