Gene variant linked to risk of aggressive prostate cancer

A gene variant that can be passed down through families might increase a man’s risk of developing early, aggressive prostate cancer, researchers at the University of Washington School of Medicine and the University of British Columbia report.

The findings suggest that the gene should be included in standard cancer-risk screening panels, and that men found to have these variants might consider earlier screening for prostate cancer, the researchers concluded, but added that more work is needed to guide specific screening recommendations.

The study is reported this month in the journal Cancer Discovery.

“The patients we identified in the study were diagnosed with prostate cancer at a younger age and had an aggressive form of the disease — all the hallmarks of the type of cancer you would want to screen for,” said Dr. Colin C. Pritchard, professor of laboratory medicine and pathology at the University of Washington School of Medicine. He was co-senior author of the paper that described the findings. Dr. Alexander Wyatt, associate professor, Department of Urologic Sciences, University of British Columbia, is the other senior co-author.

The gene, called CDK12, codes for a protein involved in regulating DNA repair. People’s cells carry two copies of the gene, one each inherited from their father and mother. If only one parent’s copy is defective, the cell can still make enough protein to repair DNA damage. But if both copies are defective, the cell's ability to repair DNA is impaired, which can lead to cancer.

For the study, researchers sequenced the coding region of CDK12 in tumors from 4,535 men with aggressive prostate cancer. They then compared those sequences with CDK12 sequences in the men's non-cancerous white blood cells. The DNA from white blood cells reflects the sequence the men inherited.

They found five men who had inherited one normal copy of CDK12 and one defective copy. In their cancer cells, however, the normal copies had mutated. There were clues in the cells' DNA that the normal activities of CDK12 had been disrupted, changes that could lead to more aggressive cancers.

The researchers also found that several family members of these patients had early-onset prostate cancer, and two sisters in one of the families had ovarian cancer. The possible role of inherited CDK12 variants in ovarian cancer warrants further investigation, the researchers said.

Based on their findings, the researchers concluded that CDK12 should be included in hereditary cancer-risk panels for people who meet testing guidelines for a history of prostate cancer and other cancers. 

More research is needed to better understand the effects of the genetic variants of CDK12 and the clinical implications, the researchers said. 

Adding CDK12 to genetic risk panels would be simple to implement, Pritchard said. CDK12 is already included in gene panels that identify treatment options for patients with cancer but is not currently included in most genetic testing panels for inherited cancer risk. 

“These inherited CDK12 variants are rare and may not affect hundreds of thousands of people,” he added, “but the people who have it will want to know, as it may have important implications for their care and for their relatives.”

Pritchard co-directs the Genetics and Solid Tumors Laboratory at UW Medicine and is the program director for Cancer Precision Diagnostics at Brotman Baty Institute.

The CDK12 research was funded in part by grants from the U.S. Department of Defense (W81XWH-17-2-0043) and the National Institutes of Health (CA015704).

Written by Michael McCarthy.

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