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Accounting for genetic aspects can improve accuracy of prostate cancer screening

The accuracy of prostate-specific antigen (PSA) screening for prostate cancer may be improved by accounting for genetic aspects that cause changes in PSA levels that usually are not related to cancer, in keeping with a multi-center study led by UC San Francisco and Stanford University.

In a study publishing June 1, 2023 in Nature Medicine, UCSF researchers and their collaborators conducted a big genome-wide association study of PSA in greater than 95,000 men without diagnosed prostate cancer, which identified over 80 novel PSA-associated variants. They got down to discover whether accounting for genetic aspects that cause variations in the degrees of PSA that usually are not attributable to cancer could help improve PSA screening.



PSA levels represent the foremost diagnostic biomarker for prostate cancer. This test is widely used but not currently implemented as a part of a proper screening program. Due to its poor sensitivity and specificity, PSA testing can often result in detecting latent disease or, in some cases, missing aggressive tumors.”

Linda Kachuri, PhD, MPH, a former postdoctoral scholar within the Department of Epidemiology & Biostatistics at UCSF and lead creator of the study

The researchers leveraged these recent data to construct a genome-wide polygenic rating for PSA, measuring a person’s genetic predisposition based on genetic variations.

“The polygenic rating captured each individual’s genetic predisposition to high PSA levels,” said Rebecca Graff, ScD, UCSF assistant professor within the Department of Epidemiology & Biostatistics and considered one of the senior authors of the study. “The polygenic rating was strongly related to PSA levels in validation cohorts and was not related to prostate cancer, confirming that it reflects benign PSA variation.”

To look at whether the polygenic rating could improve the detection of clinically significant disease and reduce overdiagnosis, the researchers applied the polygenic rating correction factor to a real-world Kaiser Permanente cohort and estimated the consequences of this adjustment on the PSA thresholds used for biopsy referrals.

“We adjusted all and sundry’s PSA values based on his unique genetic profile,” explained Kachuri. “PSA values personalized in this manner usually tend to reveal changes in PSA on account of prostate cancer because they’re corrected for the influence of inherited genetics.”

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 roughly 9% of positive biopsies. A lot of the latter cancers were low-grade disease that didn’t require treatment, but there stays room to enhance the polygenic rating.

“We showed that genetic correction of PSA levels has the potential to each reduce unnecessary biopsies and improve our ability to detect tumors with a more aggressive profile,” commented Kachuri. “We hope that our findings represent a step forward in developing informative screening guidelines and reducing the diagnostic gray area in PSA screening.”

While the study was very large, almost 90% of the participants were of predominantly European ancestry. In keeping with Kachuri, this represents a key limitation since the composition of the study doesn’t fully reflect the patient population impacted by prostate cancer. “We hope to have the ability to share findings soon from our efforts to conduct larger and more diverse studies of PSA genetics,” she said.

Source:

Journal reference:

Kachuri, L., et al. (2023) Genetically Adjusted PSA Levels for Prostate Cancer Screening. Nature Medicine. doi.org/10.1038/s41591-023-02277-9.

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