Germline Genetic Test to Make PSA Screening More Accurate

The prevalent screening test for prostate cancer - measuring prostate-specific antigen (PSA) levels - frequently produces false positives. While high PSA levels may indicate prostate cancer, other factors unrelated to cancer like inflammation, infection, an enlarged prostate, or simply aging can also cause elevated readings. As per one study, only about one-third of men with raised PSA levels were found to have prostate cancer upon biopsy. Moreover, 15% of men with normal PSA levels were later diagnosed with the disease. Scientists are now attempting to refine the PSA screening process by calibrating PSA levels to individual genetics, a move that could substantially reduce misdiagnosis and more accurately predict the aggressive disease. Such a customized screening process would require a germline genetic test in addition to the regular blood-based PSA test, using saliva, blood, or cheek swab samples to identify inherited genetic variants influencing PSA levels.

To delve deeper into the genetic factors influencing PSA level variations, scientists at Stanford Medicine (Stanford, CA, USA) collaborated with other experts to analyze the genomes and PSA levels of 95,768 men without prostate cancer. These data, mainly from men of European descent, were gathered from previous studies. The current issue with PSA screening is similar to an engineering signal-to-noise problem where the required output is mixed with background noise. The scientists' analysis suggested that genetics unrelated to cancer determined about 30% to 40% of the variations in PSA levels. By distinguishing normal variations, the scientists aim to make a more accurate assessment of when a PSA test could indicate prostate cancer.

The researchers identified 128 sites in the genome that influence inherent PSA levels. They formulated a method to measure PSA that considers an individual's normal genetic variations at these sites — this is referred to as a PSA polygenic score. This score was then tested on data from another group of nearly 32,000 men without prostate cancer, revealing that the score could predict nearly 10% of the variation in PSA levels. However, it was significantly more effective in men of European descent than in men of East Asian or African descent. Upon applying their score to a group comprising both men with and without prostate cancer (confirmed by biopsy), the researchers discovered that approximately 30% of men could have avoided a biopsy.

The adjusted PSA levels showed particular improvement in detecting aggressive prostate cancer, though this advantage was observed only in men of European ancestry. Conversely, the adjusted PSA levels would have failed to identify about 9% of positive biopsies. The majority of these missed cases were slow-growing tumors that might not require treatment, but these misclassifications suggest further scope for improving the score. The team is currently planning a more extensive study involving a more diverse group of men, as the polygenic score was developed primarily using data from men of European descent.

“A polygenic score is a quantitative way of summarizing someone’s genetic predisposition for a trait in a single value,” said Linda Kachuri, PhD, an assistant professor of epidemiology and population health and the lead author of the study. In this case, the trait is a higher baseline PSA level. “What we’re really worried about are those aggressive cases, so the fact that we’re able to show that genetically adjusted PSA is more predictive of aggressive disease is really promising.”

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Stanford Medicine