Researchers have singled out mutations in 11 genes associated with aggressive types of prostate cancer, according to a novel study published by Darst et al in JAMA Oncology. The new findings may lead to improvements in diagnosis and treatment.
Background
Currently, oncologists use genetic tests to help personalize care for certain patients with aggressive prostate cancer. The results of the tests can inform treatment—including with one class of targeted therapies that has proved effective against some inherited prostate cancers—and encourage genetic screenings among the patients’ family members so that they have the chance to reduce their cancer risk and work with physicians to be more vigilant in early detection.
Study Methods and Results
In the new study, the researchers analyzed blood samples from 18 studies involving 9,185 patients who had aggressive prostate cancer and 8,361 who did not have aggressive prostate cancer. They then sequenced the entire set of protein-coding genes among almost one-third of the patients involved in the study. They used the blood samples from the remaining patients to examine a subset of 1,749 genes—including 200 genes involved in DNA repair—that either had previously been associated with cancer or presented as likely candidates.
The researchers uncovered mutations associated with a higher risk of aggressive prostate cancer that are not currently included on genetic test panels and discovered that some genes that are currently part of the panels may not be linked to aggressive disease. The eleven genes that emerged as having mutations significantly linked to aggressive prostate cancer included BRCA2, known for its connection to breast cancer.
“Very large studies are needed to inform the creation of gene panels used for testing,” explained senior study author Christopher Haiman, ScD, Professor of Population and Public Health Sciences and the AFLAC Chair in Cancer Research at the Keck School of Medicine as well as Co-Leader of the Cancer Epidemiology Program at the Norris Comprehensive Cancer Center at the University of Southern California. “Some of the genes in these panels were based on small studies and were not associated with prostate cancer in our study.”
He continued: “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.”
Conclusions
The researchers suggested that the subset of genes, as well as those currently screened in genetic tests found not to be linked serious disease, could influence screening and precision medicine techniques for patients with prostate cancer.
They also found that some patients who didn’t have aggressive disease presented with the mutations discovered in the study.
“This suggests that mutations in these [patients] may put them at greater risk for their cancer later becoming more advanced. While screening is focused on [patients] 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,” Dr. Haiman highlighted.
The researchers indicated that their findings came with two important caveats: some mutations that drive the risk of aggressive prostate cancer may be so rare that much larger studies may be needed to better understand which genes should be included in the genetic tests, and the findings may differ in further studies assessing patients other than those of European descent who were involved in the study.
“It will be important for similar efforts to take place in [patients] of African ancestry,” stressed Dr. Haiman. “These genes and perhaps others may be important, so additional work needs to be done in other populations,” he concluded.
Disclosure: The research in this study was supported by the National Institutes of Health and the Andy Hill CARE Foundation. For full disclosures of the study authors, visit jamanetwork.com.
