Study identifies 11 gene mutations linked to aggressive prostate cancer

A new study published in JAMA Oncology identified 11 gene mutations associated with aggressive types of prostate cancer.^1,2

In the study, 7.0% and 5.6% of patients with metastatic and aggressive disease, respectively, harbored deleterious variants of the 11 genes identified by the researchers. Of note, these deleterious variants were also carried by 2.3% of patients with nonaggressive disease.

The study, which was led by investigators in the Center for Genetic Epidemiology at the Keck School of Medicine of USC and USC Norris Comprehensive Cancer Center, found that the following genes were associated with aggressive forms of the disease: BRCA2, ATM, NBN, MSH2, XRCC2, MRE11A, TP53, RAD51D, BARD1, GEN1, and SLX4.

For their exome-sequencing genetic association study, the researchers analyzed blood samples from 17,546 prostate cancer patients of European descent enrolled across 18 studies that had been conducted in the United States, Europe, and Australia. Of these patients, 9185 had aggressive disease and 8361 patients did not. The mean age in these 2 groups was 65.1 and 63.7 years, respectively.

The investigators evaluated sequencing data and compared mutation frequency between the 2 groups of patients.

Rare deleterious variants in BRCA2 and ATM (P ≤ 1.9 × 10⁻⁶), followed by NBN (P = 1.7 × 10⁻⁴)—all known prostate cancer risk genes—had the strongest association with aggressive or metastatic disease. The investigators found nominal evidence (P < .05) of rare deleterious variants in MSH2, XRCC2, and MRE11A being linked to aggressive or metastatic disease.

For the other 5 genes—TP53, RAD51D, BARD1, GEN1, and SLX4—the researchers wrote that although there was evidence of greater risk of aggressive disease (odd ratio ≥2), “carrier frequency differences between aggressive and nonaggressive prostate cancer were not statistically significant.”²

This is the largest prostate cancer study that examined the exome, according to the researchers, and they believe their findings can potentially inform the makeup of panels used for genetic testing in prostate cancer.

“Very large studies are needed to inform the creation of gene panels used for genetic testing,” corresponding author Christopher Haiman, ScD, holder of the AFLAC Chair in Cancer Research and professor of Population and Public Health Sciences at the Keck School of Medicine, stated in a news release.¹ “Some of the genes in these panels were based on small studies and were not associated with prostate cancer in our study. We also found evidence that other genes perhaps ought to be added. The results aren’t completely definitive, but it’s clear that more work needs to be done to determine which genes oncologists should focus on in testing.”

In the study, 7.0% and 5.6% of patients with metastatic and aggressive disease, respectively, harbored deleterious variants of the 11 genes identified by the researchers. Of note, these deleterious variants were also carried by 2.3% of patients with nonaggressive disease.

“This suggests that mutations in these people may put them at greater risk for their cancer later becoming more advanced,’” Haiman stated. “While screening is focused on men with advanced disease or a family history, finding patients with less advanced disease who carry these genetic variants may enable them to receive targeted forms of treatment earlier on.”¹

Of note, a key limitation of the research identified by the authors is that the study only included patients of European descent.

“It will be important for similar efforts to take place in men of African ancestry,” stated Haiman, who is also co-leader of the Cancer Epidemiology Program at USC Norris cancer center. “That’s very important. These genes and perhaps others may be important, so additional work needs to be done in other populations.”¹

References

1. Mutations in 11 genes associated with aggressive prostate cancer identified in new research. Published online September 21, 2023. Accessed October 3, 2023. https://keck.usc.edu/mutations-in-11-genes-associated-with-aggressive-prostate-cancer-identified-in-new-research

2. Darst BF, Saunders E, Dadaev T, et al. Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer [published online ahead of print September 21, 2023]. JAMA Oncol. doi: 10.1001/jamaoncol.2023.3482