Scientists discover hidden hereditary risk driving deadly prostate cancer

Five unrelated men carrying rare genetic variants developed metastatic prostate cancer between ages 44 and 62, according to new findings from the University of British Columbia. The study identifies an unrecognized form of hereditary risk linked to inherited mutations in the CDK12 gene, offering a pathway for doctors to screen vulnerable families before tumors spread.

How Inherited Mutations Drive Disease

Published in Cancer Discovery, the research analyzed genetic data from more than 4,500 individuals with aggressive prostate cancer. While scientists previously assumed harmful CDK12 mutations arose spontaneously within tumor cells, this study demonstrates they can be passed down from parents. Researchers examined patient tumors for specific genetic patterns indicating CDK12 dysfunction to confirm the inherited nature of the condition.

“The tumors provided us with a genetic signature that pointed directly back to CDK12,” said Dr. Sofie Tolmeijer, lead author and postdoctoral fellow in the Wyatt lab. “It gave us compelling evidence that these inherited mutations were playing a direct role in causing their cancer.”

Screening Opportunities for Families

Dr. Alexander Wyatt, senior author and associate professor of urologic sciences at UBC, noted that every identified patient had already reached the metastatic stage by diagnosis. He emphasized the potential for enhanced screening to catch the disease while curative treatment options remain available. Approximately 5 to 10 percent of cancers stem from inherited genetic changes, such as BRCA1 and BRCA2 mutations, which are already used to guide preventive care.

Inherited CDK12 mutations appear significantly rarer, occurring in roughly one in 1,000 people with aggressive prostate cancer. This estimate suggests hundreds of families worldwide may carry the variant. Identifying a single carrier allows relatives to undergo testing to determine if they share the mutation.

“While this mutation is extremely rare, the discovery could be lifesaving for the families who carry it,” Tolmeijer stated. “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.”

Existing Tests Enable Rapid Adoption

The team recommends adding CDK12 to standard hereditary prostate cancer testing panels. Unlike discoveries requiring new diagnostic tools, current clinical technology can already detect these mutations. This compatibility could accelerate implementation and reduce costs compared to developing new methods.

“One of the most exciting aspects of this discovery is that we already have the technology needed to act on it,” said Wyatt, who also serves as a senior research scientist at the Vancouver Prostate Centre and 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 findings also prompt questions about ovarian cancer risks. Several affected men reported family histories of ovarian cancer, and researchers identified an additional individual with ovarian cancer carrying an inherited CDK12 mutation. That person’s tumor displayed the same characteristic genetic changes associated with CDK12 dysfunction. Further investigation is required to establish whether the mutation increases ovarian cancer susceptibility.

“With the right genetic testing and screening programs, we envision a future where no one who inherits one of these mutations dies from cancer,” Wyatt concluded.

The study, titled “Germline CDK12 Variants in Aggressive Prostate Cancer,” lists Sofie H. Tolmeijer, Corinne Maurice-Dror, Shahneen Sandhu, Claire M. de la Calle, Christian Kollmannsberger, Mohamed Adil, Catherine K. Wang, Andrew J. Murtha, Gráinne Donnellan, Nielka P. van Erp, Niven Mehra, Michael S. Hofman, Arun A. Azad, Ian D. Davis, Andries M. Bergman, Wilbert Zwart, Kim van der Zande, Lesley Seymour, Peter C. Black, Vahid Akbari, Lilian Cordova, Peter M. Lansdorp, Steven J.M. Jones, Peter S. Nelson, Elena Castro, Kasmintan A. Schrader, Gavin Ha, Heather H. Cheng, Piet Ost, David Olmos, Kim N. Chi, Colin C. Pritchard and Alexander W. Wyatt as authors. It was published on 18 September 2026 in Cancer Discovery (DOI: 10.1158/2159-8290.CD-26-0084).

Funding support came from 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 partners.