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Accounting for genetic factors that cause variations in the prostate-specific antigen (PSA) levels that are not associated with cancer could help improve screening accuracy for prostate cancer.

This is according to a large multi-centre genome-wide association study of PSA in more than 95,000 men without diagnosed prostate cancer. The study, led by UC San Francisco and Stanford University, identified over 80 novel PSA-associated variants. The researchers set out to discover whether accounting for genetic factors that cause variations in the levels of PSA that are not attributable to cancer could help improve PSA screening.

鈥淧SA 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,鈥� said Linda Kachuri, PhD, MPH, a former postdoctoral scholar in the Department of Epidemiology & Biostatistics at UCSF and lead author of the study.

鈥淏ecause of its poor sensitivity and specificity, PSA testing can often lead to detecting latent disease or, in some cases, missing aggressive tumours,鈥� Kachuri said.

Genetic predisposition

The researchers leveraged these new data to build a genome-wide polygenic score for PSA, measuring an individual鈥檚 genetic predisposition based on genetic variations.

鈥淭he polygenic score captured each individual鈥檚 genetic predisposition to high PSA levels,鈥� said Rebecca Graff, ScD, UCSF assistant professor in the Department of Epidemiology & Biostatistics and one of the senior authors of the study.

鈥淭he 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.鈥�

The researchers applied the polygenic score correction factor to a real-world Kaiser Permanente cohort and estimated the effects of this adjustment on the PSA thresholds used for biopsy referrals.

鈥淲e adjusted each person鈥檚 PSA values based on his unique genetic profile,鈥� Kachuri explained. 鈥淧SA values personalised 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.鈥�

Reducing unnecessary biopsies

Applying a correction to PSA levels improved the accuracy of biopsy referral decisions. Roughly 30% of men could have avoided biopsy, though adjusted PSA levels would have missed approximately 9% of positive biopsies. Most of the latter cancers were low-grade disease that did not require treatment, but there remains room to improve the polygenic score.

鈥淲e 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,鈥� Kachuri commented. 鈥淲e hope that our findings represent a step forward in developing informative screening guidelines and reducing the diagnostic grey area in PSA screening.鈥�

While the study was very large, almost 90% of the participants were of predominantly European ancestry. According to Kachuri, this represents a key limitation because the composition of the study doesn鈥檛 fully reflect the patient population impacted by prostate cancer. 鈥淲e hope to be able to share findings soon from our efforts to conduct larger and more diverse studies of PSA genetics,鈥� she said.

Image credit: iStockphoto.com/jamesbenet