Genetic predictors could improve PSA accuracy

Genetic predictors of normal PSA levels in healthy men could be used to improve the accuracy of PSA-based prostate cancer screening, according to findings from a joint study by researchers at the University of California, San Francisco and Kaiser Permanente, Oakland, CA.

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“The aim of the study was an effort to make PSA more accurate and valuable as a prostate cancer screening tool,” co-senior author John Witte, PhD, of UCSF, told Urology Times. “We were basically trying to obtain personalized PSA levels whereby each person has a specific cutoff that reflects their constitutional PSA levels.”

Dr. Witte explained that while PSA tests for prostate cancer were once considered valuable for early cancer detection, that thinking has changed over the last 5 years. Some studies have shown that the tests are not sensitive enough and frequent false positives lead to too many unnecessary medical procedures.

In that time, the use of the test has decreased and the number of prostate cancer diagnoses has dropped, but Dr. Witte noted that the genome-wide association study (GWAS) gives notion that the PSA test could once again regain its place in cancer prevention by factoring in genetic variations that affect the amount of PSA different men naturally produce.

The study consisted of 28,503 men from the Kaiser Permanente cohort and an additional 17,428 men from replication cohorts, with the aggregate representing nearly half a million PSA tests going back as far as 25 years.

“This was a very large study of tens of thousands of subjects and hundreds of thousands of PSA levels, primarily in a Kaiser cohort, but also replicated in other study populations,” Dr. Witte said.

By having access to such a rich study population, the authors were able to identify 40 genetic regions, or loci, that together predict nearly 10% of normal variation in PSA levels in men who do not have cancer.

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The results, posted online in Nature Communications (Jan. 31, 2017), revealed that a large number of genetic variants exist for PSA levels independent of prostate cancer. Dr. Witte said that such genes provide an avenue for personalized PSA levels.

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“The strength of the associations was phenomenal. The large number of highly significant genes is unusual for a typical GWAS. The large numbers were due to our studying so many men and so many PSA levels,” Dr. Witte said.

The authors also found that the rest of the genomic sites registered an additional 32% of normal PSA variation, though the study was not sensitive enough to identify the specific genetic loci responsible for this additional variation.

Dr. Witte said that by understanding a patient’s genetic predisposition to high PSA, it could allow physicians in the future to better evaluate test results that predict the patient’s actual risk of prostate cancer. This could be done either by normalizing the results of PSA screens based on each individual’s natural PSA levels or by adjusting the threshold used to determine whether a test result should trigger further testing, such as a prostate biopsy.

With the results in, Dr. Witte believes further research is warranted and the next step is to test personalized PSA levels to see whether personalization works (ie, non-diseased are less likely to get biopsied and vice-versa). By doing so, even more genetic predictors of PSA levels are likely to be uncovered.

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