One of the largest research efforts studying genes associated with prostate cancer reveals that mutations in 11 genes are associated with aggressive disease. The study, which analyzed samples from 17,500 cancer patients and published in JAMA Oncology, found mutations in several genes not already included in common prostate cancer genetic testing panels.
Combining information from 18 studies conducted in the U.S., Europe, and Australia, the research team analyzed blood samples from prostate cancer patients of European descent—9,185 of whom had aggressive disease and 8,361 who did not—then compared the frequency of mutations among the two groups.
In the first stage of their investigations, the researchers sequenced the protein-coding genes among nearly a third of the participants. In the second stage, the researchers used samples from the remaining participants to zoom in on a subset of 1,749 genes that either had previously been associated with cancer or showed up as likely candidates in the first stage.
The 11 genes that emerged as having mutations significantly linked to aggressive prostate cancer include BRCA2, also known for its connection to breast cancer. The list of genes, as well as those currently screened in genetic tests found not to be linked to serious disease, could influence individualized treatment for prostate cancer, as well as screening.
“Most of the studies looking at genes associated with prostate cancer have not been able to look at individual genes to see if they’re associated with aggressive prostate cancer,” says first author Burcu Darst, PhD. “We found that some have been associated with prostate cancer risk, and some of them are potentially novel genes, but because we have a bigger sample size, we’re able to say with a little bit more confidence that these could really be important genes to include in gene panels.”
The strongest evidence of association with aggressive or metastatic prostate cancer was noted for rare deleterious variants in known risk genes BRCA2 and ATM, followed by NBN. This study found nominal evidence of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk but carrier frequency differences between aggressive and non-aggressive prostate cancer were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with non-aggressive, 5.6% with aggressive, and 7.0% with metastatic prostate cancer.
The findings suggest some potential avenues for applying this new discovery. First, men who are found to carry these variants —even if they do not have prostate cancer currently—may decide to initiate PSA screening in the first place, or to start screening earlier. Currently, PSA screening guidelines recommend commencing at age 45. “Men who carry these variants could potentially benefit from screening earlier than that,” says Darst.
In addition, among men who are diagnosed with prostate cancer, it could inform their future risk for advancing to more aggressive prostate cancer. “So maybe that could determine whether or not they want to go on active surveillance or receive treatment to cure the prostate cancer before it becomes aggressive,” adds Durst. Finally, in men with metastatic prostate cancer, it could have implications for whether or not they are going to respond well to certain treatments. A specific example is that cancers with BRCA2 mutations, the most well-known prostate cancer predisposition gene, are widely known to respond to PARP inhibitors. The genes TP53, ATM, MSH2, are also associated with clinically-aggressive prostate cancer and/or response to PARP inhibitors or immune checkpoint inhibitors.
The authors note two important study caveats. One is that, despite its large size, some mutations that drive risk for aggressive prostate cancer are so rare that even bigger studies are needed to validate their role in disease development. The other limitation is the findings may differ outside of the population under investigation, who are people of European descent.
