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Prostate Cancer Meta-Analysis Leads to New Risk Loci, Polygenic Risk Score

NEW YORK (GenomeWeb) – Members of a large, international team documented dozens of new prostate cancer-associated loci in a study published in Nature Genetics today.

For their meta-analysis, the researchers focused on almost 79,200 individuals with prostate cancer and more than 61,100 without, uncovering 63 risk loci not reported previously. The study builds on more than 100 prostate cancer-associated loci identified in the past, highlighting to a new locus with ties to early-onset forms of the disease.

Using new and known risk variants, which together account for an estimated 28 percent of familial prostate cancer risk, the team put together a polygenic risk score that appeared to identify men with the most pronounced prostate cancer risk.

"[W]e have uncovered vital new information about the genetic factors that can predispose someone to prostate cancer, and, crucially, we have shown that information from more than 150 genetic variants can now be combined to provide a readout of a man's inherited risk of prostate cancer," co-senior author Rosalind Eeles, an oncogenetics researcher at the Institute of Cancer Research London, said in a statement.

"We now hope to begin a small study in GP practices to establish whether genetic testing using a simple spit test could select high-risk men who might benefit from interventions to identify the disease earlier or even reduce their risk," Eeles added.

She and her colleagues began by using a custom, high-density OncoArray developed for the "Elucidating Loci Involved in Prostate Cancer Susceptibility" project to genotype 46,939 prostate cancer patients of European ancestry and 27,910 unaffected individuals from the same population, using samples collected for 52 prior studies. They analyzed those cases and controls alongside genotyping profiles for 32,255 more European individuals with prostate cancer and 33,202 without.

The search led to 65 suspicious loci, which the team whittled down to 63 after removing variants in possible linkage with one another. This risk set included 62 sites implicated in prostate cancer risk overall, along with a single variant showing ties to early-onset prostate cancer.

The researchers went on to assess the distribution of these variants in the genome, and their potential influence over prostate-specific antigen levels (PSA) and other pathways implicated in prostate cancer from past studies.

The authors also established a new polygenic risk score comprised of the 62 general prostate cancer risk loci and 85 replicated loci from prior studies. They estimated that men scoring in the top 1 percent with that tool are at roughly 5.7-fold higher prostate cancer risk than men in the general population. Prostate cancer risk appeared to be nearly 2.7 times higher than usual for men scoring in the top 10 percent on the polygenic risk score.

"Our novel associations highlight several biological pathways that warrant further investigation," they wrote, noting that a high polygenic risk score "can be used to improve the identification of men at high risk for [prostate cancer] and therefore inform PSA guidelines for screening and management to reduce the burden of over-testing."

For a related paper appearing online today in Nature Communications, some members of the same team set out to fine map 84 prostate cancer-associated loci from past studies with the help of meta-analysis summary data and a Joint Analysis of Marginal summary statistics algorithm.

"We identify a catalogue of variants and further prioritize within this set through functional annotation, to assist identification of putative causal variants," authors of that study wrote. "This refined credible set of variants explains a substantially larger proportion of the estimated familial relative risk of [prostate cancer] compared with the original GWAS tags."