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

Author

Listed:
  • William D. Dupont

    (Vanderbilt University Medical Center)

  • Joan P. Breyer

    (Vanderbilt University Medical Center
    Veterans Administration)

  • W. Dale Plummer

    (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
    Veterans Administration)

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.

Suggested Citation

  • William D. Dupont & Joan P. Breyer & W. Dale Plummer & Sam S. Chang & Michael S. Cookson & Joseph A. Smith & Elizabeth E. Blue & Michael J. Bamshad & Jeffrey R. Smith, 2020. "8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15122-1
    DOI: 10.1038/s41467-020-15122-1
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