Researchers at the University of British Columbia have identified a rare inherited mutation associated with aggressive prostate cancer developing at a relatively young age.
The findings, published in Cancer Discovery, suggest that inherited mutations in the CDK12 gene may represent a previously unrecognized form of hereditary prostate cancer. The discovery could support the expansion of genetic testing programs and help identify families who may benefit from earlier and more intensive cancer screening.
A Rare Mutation With Serious Consequences
Most cancers develop as genetic changes accumulate during a person’s lifetime. However, approximately five to 10 percent are associated with inherited mutations that can be passed between generations.
Mutations in genes such as BRCA1 and BRCA2 are among the best-known examples. These mutations can increase the risk of several cancers, including breast, ovarian, pancreatic, and prostate cancer, and their identification has helped establish screening and prevention programs for people with inherited cancer susceptibility.
The new study indicates that CDK12 may also serve as an inherited warning sign for aggressive prostate cancer.
Researchers analyzed genetic data from more than 4,500 people with aggressive prostate cancer and identified five unrelated men who carried 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 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.”
Tracing the Genetic Signature Back to CDK12
The international study brought together researchers from UBC, BC Cancer, Vancouver Coastal Health Research Institute, the University of Washington, and institutions in Australia, the Netherlands, Spain, and Belgium.
Previously, harmful CDK12 mutations were thought to occur only within tumour cells and were not considered inherited cancer-predisposition mutations.
To determine whether the inherited mutations were directly contributing to cancer development, the researchers examined the tumours for a characteristic genetic pattern associated with the loss of normal CDK12 function.
“The tumours provided us with a genetic signature that pointed directly back to CDK12,” said lead author Sofie Tolmeijer, a postdoctoral fellow in the Wyatt laboratory.
“It gave us compelling evidence that these inherited mutations were playing a direct role in causing their cancer.”
An Opportunity to Identify Families Before Cancer Spreads
Inherited CDK12 mutations were detected in approximately one out of every 1,000 people with aggressive prostate cancer. Although the mutation is uncommon, the researchers estimate that it could affect hundreds of families worldwide.
The identification of an inherited mutation in one person may also provide important information for relatives who could carry the same genetic change.
“While this mutation is extremely rare, the discovery could be lifesaving for the families who carry it,” Dr. Tolmeijer said.
“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.”
Researchers Call for Expanded Genetic Testing
The investigators said the findings support including CDK12 in standard hereditary prostate cancer genetic testing panels.
Existing clinical testing technologies are already capable of detecting CDK12 mutations. This could allow the findings to be incorporated into clinical practice without requiring the development of an entirely new testing platform.
“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 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.”
A Possible Link to Ovarian Cancer
The study also raised the possibility that inherited CDK12 mutations may be associated with an increased risk of ovarian cancer.
Several patients included in the study had family histories of ovarian cancer. The researchers also identified an individual with ovarian cancer who carried an inherited CDK12 mutation. The person’s tumour showed the same characteristic genetic changes associated with CDK12 dysfunction.
Further investigation will be needed to determine the full range of cancers that may be associated with inherited CDK12 mutations and to define the most appropriate screening strategies for affected families.
“With the right genetic testing and screening programs, we envision a future where no one who inherits one of these mutations dies from cancer,” Dr. Wyatt said.
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, the U.S. National Institutes of Health, the BC Cancer Foundation, and other funding partners.
Written by Nare Hovhannisyan, MD
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