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Decode-led Team IDs Low Frequency Prostate Cancer Risk Variant

NEW YORK (GenomeWeb News) – A rare variant on chromosome 8 contributes to prostate cancer risk in men from European populations, according to a new genome-wide association study in Nature Genetics.

For the analysis, an international team led by investigators at Decode Genetics looked for relatively low-frequency variants with ties to prostate cancer, using information on SNPs that were directly genotyped in Icelanders, assessed through in silico genotyping, or imputed from whole-genome sequence data on individuals from the same population.

The search led to new variants on a chromosome 8 region, including one fairly rare SNP that was the main focus of the researchers' follow-up analyses. While the SNP fell in a chromosome 8 region linked to the disease in the past, they reported, it appears to be largely independent of those SNPs.

Moreover, data from prostate cancer cases and controls in the Icelandic population and other populations of European descent hint that the SNP is linked to a slightly younger age of prostate cancer diagnosis — and that it has somewhat stronger ties to prostate cancer than common variants identified in the past.

"The risk profile of this new variant differs from other risk variants discovered by GWAS in being rare and conferring greater risk of the disease," senior author Kari Stefansson, a University of Iceland researcher and Decode's founder and CEO, and co-authors wrote.

Dozens of common variants have been implicated in prostate cancer through GWAS focused on SNPs that can be genotyped using existing commercial arrays, the study's authors explained, though the level of risk associated with each tends to be moderate or low.

For the current study, the researchers decided to focus on finding prostate cancer-associated variants that occur less frequently in the population, as they suspected that those rarer variants might have a more pronounced influence on disease risk.

To explore that possibility, the team relied on information at SNPs that had been directly genotyped in more than 71,700 Icelanders using one of several Illumina arrays. It also drew on sequence data for 1,795 Icelandic individuals whose genomes have been sequenced to at least 10-fold coverage depth as part of an ongoing effort aimed at whole-genome sequencing on 2,500 Icelanders.

For almost 296,500 more Icelandic individuals who had not been directly sequenced or assessed by arrays, researchers used family information as a means of imputing genotypic insights.

Together, this information helped the team track down hundreds of prostate cancer-associated SNPs during the discovery stage of the study, which focused on 5,141 Icelandic men with prostate cancer and 54,444 unaffected male controls from the same population.

These variants centered around regions of chromosomes 8 and 17 that have been implicated in prostate cancer in the past, study authors explained, prompting further analyses to look for new variants with independent ties to disease risk.

After narrowing in on a pair of chromosome 8 SNPs, the team tested both variants in five groups of prostate cancer cases and controls of European descent from Europe, the US, and the UK. Both variants had significant ties to prostate cancer risk in those cohorts.

But neither appeared to be polymorphic in individuals non-European ancestry, based on the researchers' analyses of 498 individuals with prostate cancer from Hong Kong and 467 African-American controls from Chicago.

For their subsequent analyses, investigators focused in on one of the two chromosome 8 variants, known as rs188140481. That SNP is slightly closer to the telomeric end of chromosome 8 than the common variants associated with prostate cancer in the past, they noted.

More research is needed to determine the functional role of the new variant. But results so far suggest that it is linked to a higher risk of prostate cancer in European populations than common variants found through previous GWAS. And in European prostate cancer cases considered for the current study, individuals who carried the SNP were diagnosed with the disease more than a year earlier, on average.