1. Fuerst, Mark L.

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Predicting genetic risk of lethal prostate cancer with a scoring algorithm that incorporates 290 genetic variants might inform individualized decisions about screening. The scoring algorithm accurately identified people with high or low lifetime risks of developing metastatic prostate cancer or dying from the disease.

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Genetic scores may provide an objective measure of a man's risk of dying from prostate cancer, which might be especially useful in men of African ancestry, who have a higher average risk of prostate cancer death. Based on the scoring algorithm, men with African ancestry had the highest risk of developing metastatic prostate cancer and dying of the disease.


Prostate-specific antigen (PSA) tests may not accurately predict the risk of developing aggressive forms of prostate cancer, which has led researchers to develop more precise tests. Because prostate cancer is one of the most heritable cancers, variations in a person's genetic makeup may contribute greatly to the risk for disease.


"While most prior genetic studies have focused on men of European ancestry, our scoring algorithm is a measure of risk of dying of prostate cancer in a diverse population of military veterans," said lead author Meghana Pagadala, of the VA Health Care System in La Jolla, Calif., and an MD/PhD candidate at the University of California, San Diego. "Even accounting for family history and ancestry, the scoring algorithm provided powerful additional information about a man's risk of death due to prostate cancer."


Researchers set out to determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with the risk of metastatic or fatal prostate cancer in a racially and ethnically diverse population. Pagadala presented the results of the study at the 2022 ASCO Genitourinary Cancers Symposium (Abstract 155).


The algorithm incorporates 290 previously identified gene variants associated with prostate cancer risk. Presence or absence of each variant and the patients' ages were applied to the algorithm to generate an optimal model for association with age at prostate cancer diagnosis.


About the Study

The researchers analyzed data from the Million Veteran Program, a multi-ancestry population of more than 500,000 individuals participating in the VA health care system. About 600,000 of the enrollees receiving medical care at 63 facilities nationwide were male, and researchers were able to obtain clinical information for nearly 97 percent of those men. About 425,000 had a European ancestry and about 105,000 had an African ancestry, while the remaining had either Asian or Hispanic heritages. The 513,997 men, median age 69 years, in the study gave consent to donate blood for genotyping.


"Compared to other tests of risk, the scoring algorithm uses nearly 300 variants linked to inherited genetic information, whereas some currently available commercial tests rely on expression of just a dozen or so cancer-related genes and a handful of reference genes," Pagadala explained. "One advantage to heritable genetic information is that it does not change through a person's lifetime, whereas tumor gene expressions can be highly variable and are only available once a man has already developed the disease. This algorithm was developed to predict risk of prostate cancer at different ages."


Key Findings

Risk of death was 4.41 times higher for men in the top 20 percent of scores as determined by the algorithm compared to those whose genetic risk score was in the lowest 20 percent. The risk for developing prostate cancer or having the disease metastasize was 5.66 times higher and 4.18 times higher for those in the top 20 percent of risk scores compared to those in the lowest 20 percent, respectively.


The most pronounced outcomes based on a PHS290 score were in people with African ancestry, who had a 1.84 times greater risk for developing prostate cancer compared to people of European ancestry. There was a 2.27 times greater risk for prostate cancer metastasis and a 1.97 times greater risk for death based on risk scores in people of African ancestry compared to those of European ancestry.


Risk for people of Hispanic ancestry tracked closely with those of European ancestry. The numbers of men with Asian ancestry were too small to determine a reliable estimate of risk. Family history of prostate cancer also conferred a greater risk of developing and dying of prostate cancer, Pagadala said.


The researchers hope to identify more ancestry-specific prostate cancer risk variants and better understand how to incorporate ancestry into estimating genetic risk. In addition, they plan to look at the interaction of genetic risk and environmental factors, Pagadala said. The scoring algorithm is not yet commercially available.


ASCO expert in genitourinary cancers, Robert Dreicer, MD, MS, Deputy Director of UVA Cancer Center, commented: "Current prostate cancer screening recommendations rely on family history, as well as race and ethnicity-factors which often don't fully capture a person's risk of developing or dying from prostate cancer. This new study suggests that an extensive genetic risk score could be an effective tool to guide screening decisions by identifying people at high or low risk of developing metastatic prostate cancer. Importantly, this tool been validated in a diverse population."


Mark L. Fuerst is a contributing writer.