New form of hereditary prostate cancer can cause aggressive disease at a young age

Researchers at the University of British Columbia 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. 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." 

Dr. Alexander Wyatt, senior author, associate professor of urologic sciences, UBC faculty of medicine and UBC President's Excellence Chair in Precision Oncology

Uncovering a hidden hereditary risk 

The study was an international collaboration between researchers at UBC, BC Cancer, Vancouver Coastal Health Research Institute 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," said lead author Dr. Sofie Tolmeijer, a postdoctoral fellow in the Wyatt lab. "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," said Dr. 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," said Dr. Wyatt, who is also a senior research scientist at the Vancouver Prostate Centre and senior scientist at BC Cancer. "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," said Dr. Wyatt.