Posted: Friday, July 7, 2023
Accounting for genetic factors that may cause changes in prostate-specific antigen (PSA) levels not associated with cancer may improve the accuracy of PSA screening for prostate cancer, according to new research published in Nature Medicine. In a large, multicenter study, Linda Kachuri, PhD, MPH, of the University of California, San Francisco (UCSF), and colleagues observed that personalizing individuals’ PSA values based on their unique genetic profiles has the potential to both reduce unnecessary biopsies and improve detection of tumors with more aggressive profiles.
“Because of its poor sensitivity and specificity, PSA testing can often lead to detecting latent disease or, in some cases, missing aggressive tumors,” said Dr. Kachuri, in a UCSF press release. “We hope that our findings represent a step forward in developing informative screening guidelines and reducing the diagnostic gray area in PSA screening.”
The researchers conducted a genome-wide analysis of PSA levels in 95,768 cisgender men who were never diagnosed with prostate cancer, and they identified 128 PSA-associated variants. Using these data, the investigators built a genome-wide polygenic score for PSA that measures an individual’s genetic predisposition to high PSA levels. They then applied the score to a real-world Kaiser Permanente cohort and found that roughly 30% of the men could have avoided biopsy. The genetically adjusted PSA level also improved detection of aggressive disease (odds ratio [OR] = 3.44; P = 6.2 × 10-14; AUC = 0.755).
Acknowledging that the score-adjusted PSA levels would have missed approximately 9% of positive biopsies—most of which were low-grade disease that did not require treatment—the team noted that further study presents opportunities to improve the polygenic score. And, although the study was very large, almost 90% of the participants were of predominantly European ancestry, necessitating larger and more diverse studies of PSA genetics.
Disclosure: For full disclosures of the study authors, visit nature.com.