Photo Credit: National Cancer Institute
Scientific Frontline: Extended "At a Glance" Summary: Hereditary CDK12 Mutation in Prostate Cancer
The Core Concept: Researchers have identified a rare, inherited mutation in the CDK12 gene that predisposes individuals to aggressive, metastatic prostate cancer at a relatively young age. This discovery expands the understanding of hereditary cancer risks beyond traditional markers like BRCA1 and BRCA2.
Key Distinction/Mechanism: Unlike previous assumptions that harmful CDK12 mutations arise only spontaneously within tumor cells, this study confirms they can be inherited; tumors associated with these mutations exhibit a distinct genetic signature indicating the gene has ceased to function correctly.
Major Frameworks/Components:
- Identification of germline (inherited) CDK12 mutations in five unrelated men with metastatic prostate cancer.
- Utilization of a distinctive genetic "fingerprint" left by non-functional CDK12 to confirm hereditary causality.
- Evidence suggesting potential cross-cancer risk, with findings indicating a possible link to an increased risk of ovarian cancer.
- Collaboration between UBC, BC Cancer, the Vancouver Coastal Health Research Institute, the University of Washington, and international partners.
Branch of Science: Oncology, Urologic Sciences, Genetics, and Molecular Biology.
Future Application: The incorporation of CDK12 into standard genetic testing panels for hereditary prostate cancer screening. Because existing clinical technology can already detect these mutations, the integration into routine diagnostic care is projected to be efficient and rapid.
Why It Matters: This discovery enables the identification of at-risk families before the disease progresses to a metastatic state, providing an opportunity for early, potentially curative intervention and systematic family screening.
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 5 to 10 percent 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,” said senior author Dr. Alexander Wyatt, associate professor of urologic sciences in the UBC Faculty of Medicine and UBC President’s Excellence Chair in Precision Oncology. “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 among researchers at UBC, BC Cancer, the 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 tumor 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 tumors 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 Center and a 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 tumor 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.
Funding: The study was supported by the Prostate Cancer Foundation, the Terry Fox Research Institute, the Canadian Cancer Society, the Canadian Institutes of Health Research, Michael Smith Health Research BC, the US National Institutes of Health, the BC Cancer Foundation, and other funding partners.
Published in journal: Cancer Discovery
Title: Germline CDK12 variants in aggressive prostate cancer
Authors: 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
Source/Credit: University of British Columbia | Brett Goldhawk
Edited by: Scientific Frontline
Reference Number: ongy071026_01