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Decode-Led Study Suggests Genetics May Refine PSA Testing

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – An international research group led by investigators at Decode Genetics reported online today in Science Translational Medicine that they have uncovered genetic loci that they believe will be useful for improving the accuracy of prostate cancer screening based on prostate-specific antigen, or PSA, levels.

The researchers used genome-wide association and replication studies involving more than 16,000 men from Iceland and the UK to find half a dozen loci on five chromosomes that correspond to PSA levels. Their subsequent analyses of almost 47,000 more men with or without prostate cancer from five countries indicated that two of the loci are linked to PSA level alone while four are associated with both PSA levels and prostate cancer.

Moreover, their findings suggest that incorporating information on variants at such loci would lead to the reclassification of at least some men who would or would not be considered candidates for prostate cancer biopsies based on PSA data alone.

"Like virtually every protein in the body, PSA levels vary between individuals according to SNPs that regulate gene expression," Decode CEO and University of Iceland researcher Kari Stefansson, who was senior author on the paper, said in a statement. "The SNPs reported today enable us to personalize PSA thresholds, thereby changing the recommendation on whether to biopsy for a substantial proportion of men."

"Detected early, prostate cancer can be treated with near total success," he added. "The challenge is to more effectively risk stratify the population, identifying and biopsying those at high risk and with aggressive disease while minimizing the number of negative biopsies we perform."

Because prostate cancer often coincides with elevated PSA levels in the blood, PSA testing is commonly used to screen for the disease. Nevertheless, since benign conditions such as prostate hyperplasia, inflammation, or other urological problems can also bump up PSA levels, researchers noted, higher than average PSA levels don't specifically point to prostate cancer, and looking at this measure alone can miss some cancer cases.

"One approach to increase the specificity and sensitivity of the PSA test is to work out a model that defines the 'normal' PSA value for a given man," they wrote, noting that age and sequence variants influencing PSA-related gene expression are among the factors that should be considered when trying to determine each individual's baseline PSA levels.

In an effort to uncover genetic variants influencing PSA levels, Stefansson and his co-workers first assessed data for 15,757 men from Iceland and 454 men from the UK who had not been diagnosed with prostate cancer, but for whom PSA information was available. Genotype data had either been determined using Illumina 317K or 370K HumanHap arrays or was inferred in silico from relatives' genotype data, they explained.

In the process, they uncovered six SNPs that apparently correspond to PSA levels, including two loci on chromosome 10 and individual loci on chromosomes 5, 12, 17, and 19. The strongest signal came from a pair of chromosome 19 SNPs in the KLK3 gene, which codes for PSA itself, the researchers noted.

A follow-up study of 5,325 men with prostate cancer and 41,417 unaffected controls from Iceland, the Netherlands, Spain, Romania, and the US, meanwhile, indicated that two of the new loci — SNPs at 10q26 near the FGFR2 gene and 12q24 locus variants in linkage disequilibrium with SNPs in the TBX3 gene — coincide with PSA levels alone, while the remaining four PSA-associated loci are also tied to prostate cancer risk.

And when they focused in on about 2,300 Icelandic men and 1,400 British men who had had prostate biopsies, the team found that variants from all six loci were over-represented in those biopsied compared to the controls, though only about half the Icelandic and roughly a third of the British men biopsied were actually diagnosed with cancer.

Moreover, they noted, biopsied men diagnosed with cancer tended to have fewer PSA-related variants in the KLK3, FGFR2, and TBX3 genes than those with negative biopsies, consistent with the notion that SNPs in these genes may jack up PSA levels even in the absence of disease.

In addition, their subsequent experiments suggest that adding in data on PSA-associated loci would lead to reclassifications of some six to seven percent of men selected for prostate biopsies in Iceland compared with PSA measurements alone.

"In combination with information about age, ethnicity, and family history of the disease, estimates of the effect of genetic variation on prostate cancer risk and PSA levels could lay a foundation for the development of individual prostate cancer screening strategies that would have the ultimate goal of reducing cost and improving quality of life," the researchers concluded.

"[T]he discriminatory power of testing for these SNPs is highest when done in tandem with the SNPs associated directly with risk of the disease measured by our deCODE ProstateCancer test," Stefansson added in a statement. "We are working to swiftly incorporate these PSA markers into our testing portfolio."

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