Findings create opportunity to expand genetic screening for families at risk of aggressive cancer.
Researchers at the Vancouver Prostate Centre have identified a new form of hereditary prostate cancer that, while rare, can cause aggressive disease at a young age. The discovery paves the way for genetic testing programs that could help identify at-risk families and support early cancer detection.
While most cancers are caused by genetic changes that accumulate over a person’s lifetime, about five to 10 per cent are linked to inherited mutations that can be passed from one generation to the next.
The best-known examples are mutations in the BRCA1 and BRCA2 genes, which greatly increase the risk of developing certain cancers, including breast, ovarian, pancreatic and prostate cancer. Genetic testing for BRCA mutations has transformed cancer care, helping people at risk access early screening and prevention programs.
The new study, published in Cancer Discovery, identifies another gene — called CDK12 — that could provide a similar warning sign for aggressive prostate cancer. The researchers analyzed genetic data from more than 4,500 people with aggressive prostate cancer and identified five unrelated men carrying inherited CDK12 mutations. All five developed metastatic prostate cancer between the ages of 44 and 62.
“What’s striking is that every patient we identified with this inherited mutation had already developed metastatic disease by the time they were diagnosed,” says senior author Dr. Alexander Wyatt. “The opportunity now is to identify these families earlier and give people the chance to benefit from enhanced screening, when there are still curative treatment options.”
Uncovering a hidden hereditary risk
The study was an international collaboration between researchers at the Vancouver Coastal Health Research Institute, UBC, BC Cancer and the University of Washington, as well as institutions in Australia, the Netherlands, Spain and Belgium.
Until now, scientists believed harmful CDK12 mutations only occurred spontaneously within tumour cells and could not be inherited. To confirm that the inherited mutations were causing the cancer, the researchers looked for a distinctive genetic fingerprint left behind when CDK12 stops working.
“The tumours provided us with a genetic signature that pointed directly back to CDK12,” says lead author Dr. Sofie Tolmeijer. “It gave us compelling evidence that these inherited mutations were playing a direct role in causing their cancer.”
Although inherited CDK12 mutations were found in only about one in every 1,000 people with aggressive prostate cancer, the researchers estimate they could affect hundreds of families worldwide.
“While this mutation is extremely rare, the discovery could be lifesaving for the families who carry it,” says Tolmeijer. “Finding one person with an inherited mutation gives us the opportunity to identify other family members at risk and help them take action before cancer develops or spreads.”
Expanding genetic testing for families at risk
The researchers say the findings support adding CDK12 to standard genetic testing panels for hereditary prostate cancer. Unlike many newly discovered cancer biomarkers, existing clinical technology can already detect CDK12 mutations, providing a potentially faster and more cost-effective path to expanded testing.
“One of the most exciting aspects of this discovery is that we already have the technology needed to act on it,” says Wyatt. “Adding CDK12 to existing genetic tests is relatively straightforward, which means this discovery could move from the research lab into clinical care much more quickly.”
The study also raises the possibility that inherited CDK12 mutations may increase the risk of ovarian cancer. Several of the patients had family histories of ovarian cancer, and the researchers identified an additional person with ovarian cancer who carried an inherited CDK12 mutation and whose tumour showed the same characteristic genetic changes.
“With the right genetic testing and screening programs, we envision a future where no one who inherits one of these mutations dies from cancer.”
The study was supported by the Prostate Cancer Foundation, Terry Fox Research Institute, Canadian Cancer Society, Canadian Institutes of Health Research, Michael Smith Health Research BC, U.S. National Institutes of Health, BC Cancer Foundation and other funding partners.
Read the original story on the UBC Faculty of Medicine website.
