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Study evaluates polygenic risk score for prostate cancer risk prediction

Mar. 16, 2023, 9:53 AM

Research by Mingjian Shi, PhD, left, Jonathan Mosley, MD, PhD, Kerry Schaffer, MD, MSCI, and colleagues found that polygenic risk score does not improve prediction of aggressive prostate cancer.
Research by Mingjian Shi, PhD, left, Jonathan Mosley, MD, PhD, Kerry Schaffer, MD, MSCI, and colleagues found that polygenic risk score does not improve prediction of aggressive prostate cancer. (photo by Susan Urmy)

by Leigh MacMillan

A prostate cancer polygenic risk score (PRS) has limited utility for enhancing prostate cancer screening, according to a new study published in JAMA Internal Medicine.

Vanderbilt University Medical Center researchers led the study to evaluate whether a prostate cancer PRS, an indicator of an individual’s “burden” of prostate cancer-associated genetic variants, could improve risk prediction compared to an available clinical risk calculator. While the prostate cancer PRS improved detection of all prostate cancers, it did not improve prediction of aggressive cancers, the researchers found.

Prostate cancer is the second leading cause of cancer-associated death in men, according to the American Cancer Society. About one in eight men will be diagnosed with prostate cancer during his lifetime.

Although screening strategies based on prostate-specific antigen (PSA) and other factors have been developed, biopsies often find low-grade cancers that pose minimal risk and do not warrant therapy.

“Low-grade prostate cancer diagnoses contribute to increased health care expenditures, patient anxiety and invasive procedures with potential for serial biopsies,” said Kerry Schaffer, MD, MSCI, assistant professor of Medicine in the Division of Hematology and Oncology and co-first author of the new report. “There is strong interest in identifying biomarkers and tools to better discriminate aggressive cancers from low-grade tumors in order to guide decision-making about prostate biopsies.”

Prostate cancer is a highly heritable disease, and genome-wide association studies (GWAS) have identified numerous common genetic variants associated with increased prostate cancer risk.

“Incorporating polygenic risk scores that measure the burden of these risk-associated variants could improve risk prediction models,” said Jonathan Mosley, MD, PhD, associate professor of Medicine in the Division of Clinical Pharmacology and senior corresponding author of the study.

“We compared the performance of an extensively validated multiethnic prostate cancer PRS against a contemporary and widely utilized clinical tool, the PBCG risk calculator, to risk-stratify individuals for aggressive prostate cancer,” Schaffer said.

The PBCG (Prostate Biopsy Collaborative Group) risk calculator uses age, PSA, digital rectal exam findings, ancestry and family history to estimate the probability of finding 1) any cancer and 2) aggressive cancer in men undergoing a first prostate biopsy.

Schaffer and co-first author Mingjian Shi, PhD, staff scientist in the Department of Biomedical Informatics, led the retrospective study, which included 655 men of African and European ancestries ages 40-80 years without prostate cancer who underwent a prostate biopsy. Participants were drawn from BioVU, VUMC’s DNA biobank linked to de-identified electronic health records.

The researchers found that adding the PRS to the PBCG predictor improved discrimination for any cancer, but not for aggressive cancer.

The findings suggest that “this prostate cancer PRS has limited clinical utility currently for guiding a decision to perform a diagnostic biopsy and is inferior to current clinical tools,” Mosley said.

The authors note that strengths of their study are: using the most recently available PRS, which is based on a multiancestry GWAS, and including a study population with a broader group of ancestries and clinically relevant age range, compared to prior work.

“Although only 8% of our population is of African ancestry, we intentionally included these data in an effort to contribute to an important and evolving body of literature which includes groups that are often underrepresented in genetic studies,” Schaffer said. “As PRSs evolve in the field, research including racially diverse populations is imperative to prevent the current inequities in genomics from expanding.

“Vanderbilt researchers are participating in numerous projects related to PRS and disease risk; studies such as this highlight the importance of evaluating whether novel clinical tools actually enhance care.”

Other authors of the JAMA Internal Medicine report include John Shelley and Jeffrey Tosoian, MD, MPH, at VUMC and Linda Kachuri, PhD, and John Witte, PhD, at Stanford University. The research was supported by the National Institutes of Health (grants GM130791, CA241410). VUMC’s BioVU is supported by institutional funding, private agencies and federal grants.

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