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genetic profiling can help reduce missed prostate cancer diagnoses
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psa tests detect a protein that is linked to prostate cancer, but also other conditions, like an enlarged prostate. getty
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a new study has found a way to increase the accuracy of prostate-specific antigen (psa) screening for prostate cancer by filtering out genetic factors unrelated to cancer that may cause these levels to change.
although psa tests are commonly used to detect prostate cancer, the protein they are designed to detect is produced by both cancerous and non-cancerous tissue. there are many conditions unrelated to cancer, such as an enlarged prostate, that can increase these levels and make it difficult to determine if the disease is actually present.
prostate screening can be improved
the current study, published in the journal nature medicine, hoped to improve the results of screening by personalizing the process. to this end, the team conducted a massive genome-wide association study of psa in more than 95,000 people who had not been diagnosed with the disease.
“psa levels represent the main diagnostic biomarker for prostate cancer. this test is widely used but not currently implemented as part of a formal screening program,” said linda kachuri, lead author of the study and a former post-doctoral scholar in the department of epidemiology & biostatistics at uc san francisco. “because of its poor sensitivity and specificity, psa testing can often lead to detecting latent disease or, in some cases, missing aggressive tumours.”
prostate cancer is the fourth most common cancer in canada — and the top one among men — with an estimated 24,600 people receiving a diagnosis in 2022, according to the canadian cancer society. around 4,600 men were expected to have succumbed to the disease last year. eight provinces and three territories cover the cost of the psa test by referral without requiring symptoms, except ontario and british columbia.
in an attempt to improve the odds of accurate detection, researchers built a genome-wide polygenic score that included any genetic factors that might influence an individual’s psa levels.
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“the polygenic score captured each individual’s genetic predisposition to high psa levels,” said rebecca graff, senior author of the study and an assistant professor in the department of epidemiology & biostatistics. “the polygenic score was strongly associated with psa levels in validation cohorts and was not associated with prostate cancer, confirming that it reflects benign psa variation.”
the team then tested if these individualized polygenic scores were more efficient at detecting clinically significant cancer while reducing the risk of over-diagnosis. to do this, they applied these scores to a real-world cohort of patients and estimated the effect their adjustments had on the psa thresholds used to refer patients for biopsy.
“we adjusted each person’s psa values based on his unique genetic profile,” kachuri said. “psa values personalized in this way are more likely to reveal changes in psa due to prostate cancer because they are corrected for the influence of inherited genetics.”
they found that the corrections they applied to psa levels improved the accuracy of referral decisions: around 30 per cent of men in the cohort could have avoided getting a biopsy if their corrections had been used. they also found, however, that the adjusted psa levels would have missed around nine per cent of positive biopsies. most of the cancers that were missed were low-grade and did not require treatment but their omission revealed there is room for improvement.
“we showed that genetic correction of psa levels has the potential to both reduce unnecessary biopsies and improve our ability to detect tumours with a more aggressive profile,” kachuri said. “we hope our findings represent a step forward in developing informative screening guidelines and reducing the diagnostic grey area in psa screening.”
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although the study was large in nature, close to 90 per cent of the people involved were from european ancestry, a limitation that does not reflect the composition of prostate cancer patients. “we hope to be able to share findings soon from our efforts to conduct larger and more diverse studies of psa genetics,” kachuri said.
dave yasvinski is a writer with healthing.ca
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