B.C. researchers identify inherited mutation linked to aggressive prostate cancer in young patients

Men who inherit mutations in the gene CDK12 may be at risk of developing aggressive prostate cancer at a young age, a new study suggests. The findings support adding CDK12 to standard genetic testing screens for hereditary prostate cancer, the researchers say.Identifying people who have inherited the CDK12 mutation could let physicians diagnose or detect cancer earlier, when treatment may have a greater impact. “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, an associate professor of urologic sciences at the University of British Columbia’s faculty of medicine, in a university press release. “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.”Researchers from the University of British Columbia and institutions in the U.S., Australia, the Netherlands, Spain and Belgium analysed genetic data from 4,535 people with aggressive prostate cancer. They identified five unrelated men who had inherited CDK12 gene mutations. All five men developed CDK12-driven metastatic prostate cancer between the ages of 44 and 62. Two patients also had somatic CDK12 mutations in addition to the inherited mutation.CDK12 mutations are present in 2%-to-7% of metastatic prostate cancers. Previously, researchers considered that all mutations in CDK12 were somatic, not inherited. Researchers used a specific genetic fingerprint that CDK12 leaves behind when it stops working to confirm the inherited mutation caused the cancer. The genetic fingerprint, or signature, includes hundreds of tandem duplications. “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 lab, in the press release. “It gave us compelling evidence that these inherited mutations were playing a direct role in causing their cancer.” The discovery could help identify patients and their family members who may be at risk for aggressive prostate cancer. The researchers estimate that the inherited mutation could affect hundreds of families across the world.The results of the study also suggest that inherited CDK12 mutations may be related to ovarian cancer. Family histories of the five patients with inherited CDK12 mutations and metastatic prostate cancer revealed relatives with ovarian cancer and others with prostate cancer.Adding CDK12 to existing genetic testing panel would be straightforward, Dr. Wyatt said. Existing clinical technology can already identify CDK12 mutations.“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, who also holds a chair in precision oncology, is a senior research scientist at the Vancouver Prostate Centre and a senior scientist at BC Cancer.The study was published in Cancer Discovery.

B.C. researchers identify inherited mutation linked to aggressive prostate cancer in young patients

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