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Could newly uncovered genetic markers for prostate-specific antigen improve screening for prostate cancer?

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A new study, published recently in Nature Communications, has identified genetic predictors of prostate-specific antigen (PSA) levels in healthy men. These findings could be utilized to improve diagnostic tests for prostate cancer, reducing the occurrence of over-diagnosis.

PSA tests have previously been considered a successful method of detecting prostate cancer; however, in recent years studies have begun to question the sensitivity of the test, with frequent false positives leading to unnecessary medical procedures.

Co-senior author of the study, John Witte (University of California San Francisco; CA, USA) explained: “In the few years that PSA testing has become less popular, the use of the test has declined and the number of prostate cancer diagnoses has dropped. Disturbingly, some of the cases that are detected are now being diagnosed at a later stage, making successful treatment less likely. It’s a big conundrum for the field.”

A major issue affecting the test’s sensitivity is that the amount of PSA is not only affected by cancer but also genetic factors which lead to healthy men naturally producing the protein at different levels. The current PSA testing does not take these baseline levels into account, leading to a over-diagnosis.

The researchers, led by Stephen K Van Den Eeden (University of California San Francisco), undertook a genome-wide association study of PSA levels in 28,503 men from the Kaiser Permanente cohort, and tested for replication in an additional 17,428 samples.

Van Den Eeden commented: “The unique setting of Kaiser Permanente allowed us to link every man in the study to our electronic clinical data and determine not just that they had a test, but also the level and frequency of testing over many years.”

The group uncovered 40 genome-wide significant single-nucleotide polymorphisms for PSA, which accounted for 9.5% of natural PSA variation in men. Moreover, they uncovered additional genomic sites contributing to a further 31.7%, supporting the genetic basis of PSA levels.

The team suggested that by understanding a patients’ genetic predisposition to high PSA physicians could provide more accurate test results, either by normalizing the results of PSA screens based on natural levels, or by adjusting the threshold for further testing.

This study provides important information about genetic markers for PSA, which could be utilized to improve screening for prostate cancer and reduce over-diagnosis in the future.

Witte concluded: “Despite the flaws of PSA testing, it does have value as a diagnostic tool. If we want to improve PSA as a useful diagnostic, we need to fold personalized genetics into medical decision-making. We need to be able to tell patients – this is a high PSA value for you, not just for the average person.”

Source: Hoffmann TJ, Passarelli MN, Graff RE et al. Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer, Nat. Comms. doi:10.1038/ncomms14248 (2017) (Epub ahead of print) www.ucsf.edu/news/2017/02/405701/precision-medicine-approach-could-revive-prostate-cancer-test

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