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Study Identifies Gene Variants Associated With Aggressive Prostate Cancer


NEW YORK – In the largest genetic association study of its kind in prostate cancer, researchers identified 11 genes associated with aggressive versus non-aggressive disease, including some that are not currently included in genetic test panels.

While study author Burcu Darst, an assistant professor in the Public Health Sciences Division at Fred Hutchinson Cancer Center, cautions that larger studies are needed to confirm the results, the new research published in JAMA Oncology could better inform which genes are included in prostate cancer panels used to identify men at increased risk of aggressive disease.

"We did see in our study that a lot of men who are carrying these rare variants that are associated with aggressive disease actually are initially diagnosed with non-aggressive disease," Darst said, adding that for those patients, the insight offered by the previously unknown rare variants could impact treatment decision-making.

Darst said she became interested in prostate cancer because it represents one of the greatest areas of health disparity in the US and also has a significant heritable component. The goal of the study was to learn how to better identify which men — with or without prostate cancer — have a greater risk of developing aggressive prostate cancer.

Germline gene panel testing is used routinely to guide treatment and disease management in men with advanced prostate cancer and to assess risk and inform screening recommendations for men with a family history of cancer. Those panels typically look for mutations in genes involved in DNA repair and other cancer-driver genes such as BRCA2, BRCA1, ATM, CHEK2, and HOXB13. However, the sequencing studies used to establish these associations have been hampered by small sample sizes and have overlooked other types of gene variations. "A lot of the genes that are included [in prostate cancer panels] have not really had very strong evidence of actually being associated with prostate cancer risk," Darst said. "And there are likely a lot of genes that are just missing because the sequencing studies to date … haven't had large sample sizes."

Darst and collaborators at the Keck School of Medicine of USC and USC Norris Comprehensive Cancer Center undertook a large-scale, multistage sequencing study involving more than 17,000 men with aggressive and non-aggressive prostate cancer drawn from 18 epidemiological studies in Australia, the US, the UK, Finland, Sweden, and other European countries. The researchers conducted whole-exome sequencing in the first stage of the study in more than 5,000 patients, and in the second stage, conducted targeted gene sequencing of more than 12,000 patients. The genes selected for targeted sequencing were known to be associated with prostate cancer or cancer in general from prior studies or they had an association with aggressive prostate cancer in stage 1 of the study.

Darst said that coordinating the international group of collaborators to gather all of the samples and fund the expensive whole-exome sequencing was a challenge, but "we ended up finding that there were about 11 genes that had some good evidence of being associated with risk of aggressive compared to non-aggressive disease."

These genes included those that have been included on prostate cancer gene panels and those that have not. Of genes typically included in prostate cancer gene panels, the researchers found evidence that four — BRCA2, ATM, MSH2, and NBN — were associated with aggressive prostate cancer, with the strongest evidence linked to BRCA2, ATM, and NBN, in that order. The evidence for MSH2, though, was nominal, as well as for variants in XRCC2 and MRE11A.

XRCC2 and MRE11A have been considered candidates for prostate cancer gene panels, but have not been included, Darst noted, adding that the current study provides much stronger evidence than past ones.

Another five genes — TP53, RAD51D, BARD1, GEN1, and SLX4 — were associated with greater risk of aggressive disease, but there were no significant differences in carrier frequency between aggressive and non-aggressive disease. TP53 has been previously implicated in aggressive prostate cancer and has been used in prostate cancer gene panels. RAD51D, BARD1, GEN1, and SLX4 had limited or no previous evidence of association with aggressive prostate cancer but are included in some prostate cancer gene panels.

Collectively, deleterious variants in these 11 genes were found in 2.3 percent of patients with non-aggressive prostate cancer, 5.6 percent with aggressive prostate cancer, and 7.0 percent with metastatic prostate cancer.

Another three genes — POLK, POLH, and MSH5 — have not been previously considered as candidate prostate cancer genes, nor have they been included in panels, but in the study they emerged as genes that could be important to include on prostate panels. Meanwhile, several genes that are commonly included on panels but had low evidence in the study were PMS2, RAD51C, EPCAM, and BRIP1.

The results are significant, Darst explained, because of the large sample size, which enabled her group to make risk estimates that are likely a better representation of real individual risk for patients. "We looked at the outcomes of aggressive prostate cancer, metastatic prostate cancer, and cancer death, so we're better able to characterize the risk associated with these different outcomes," she said.

And because the study was international, she and her colleagues were also able to find some variations in the frequency of carriers for rare variants between countries. For example, variants in BRCA2, a significant risk factor for aggressive disease, had a greater odds ratio in the UK than it did for some other countries. In Finland, the association between BRCA2 variants and the risk of aggressive disease was much weaker.

More studies such as this one need to be conducted, Darst said, particularly in men of non-European ancestry, which were not included in the analysis due to a lack of data.

Men of African ancestry are at greater risk of developing and dying from prostate cancer, Darst explained, and determining whether these genes that have been identified in a predominantly European-ancestry population are also important in an African-ancestry population would be an important step to ensure that changes in screening recommendations will have equitable impacts across populations.

Based on the variability in disease-associated variant frequency observed just among men of European ancestry, Darst speculated that there could be similar or even greater variability when the sample is expanded to include men of other backgrounds. "In terms of really improving our knowledge of prostate cancer, there could be additional genes that we haven't identified yet because the carrier frequencies are even more exceedingly rare in European ancestry populations, but they're more prominent in other populations that we haven't yet investigated," Darst said, adding that it will likely require sample sizes much greater than the 17,000 used in the present study to detect them.

To that end, Darst and colleagues at other institutions have already launched a new, more ambitious effort to conduct exome sequencing on 90,000 men with prostate cancer and 500,000 controls across diverse populations drawn from multiple studies and biobanks. Darst is hoping the work will pay off by allowing them to better characterize the risk of aggressive prostate cancer and overall prostate cancer, further refine the results from this current study, and potentially discover new gene variants of significance.