When Dr. Sofie Tolmeijer looked at the genetic data from more than 4,500 men with aggressive prostate cancer, she expected to find what scientists had long assumed — that mutations in a gene called CDK12 only happened inside tumors, never inherited. Instead, she found something that would change how families might be warned about their cancer risk.
Five unrelated men in the study carried an inherited CDK12 mutation. All five developed metastatic prostate cancer between ages 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 Dr. Alexander Wyatt, senior author of the study and associate professor of urologic sciences at the University of British Columbia. "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."
The findings, published in the journal Cancer Discovery, represent a new form of hereditary prostate cancer that scientists had overlooked until now. While most cancers develop from genetic changes that happen over a lifetime, about 5% to 10% are linked to mutations passed down through families. The best-known examples are BRCA1 and BRCA2 mutations, which increase risk for breast, ovarian, pancreatic, and prostate cancers.
To confirm the inherited CDK12 mutations were actually causing these cancers, the researchers looked for a distinctive genetic fingerprint left behind when the gene stops working. "The tumors provided us with a genetic signature that pointed directly back to CDK12," said Dr. 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."
The discovery matters because CDK12 mutations can already be detected with existing clinical technology. Unlike many newly found cancer markers, this one doesn't require new tools to test for. "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," Dr. Wyatt said.
The mutation is rare — roughly 1 in every 1,000 people with aggressive prostate cancer. But the researchers believe it could affect hundreds of families worldwide. The study was an international collaboration involving UBC, BC Cancer, Vancouver Coastal Health Research Institute, the University of Washington, and institutions in Australia, the Netherlands, Spain, and Belgium.
The research also raised a new question: inherited CDK12 mutations may increase ovarian cancer risk too. Several patients had family histories of ovarian cancer, and the team found another person with ovarian cancer who carried the same mutation.
"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."