Rare inherited variants in the CDK12 gene may predispose patients to aggressive metastatic prostate cancer, according to a study published in Cancer Discovery. The findings challenge the longstanding view that pathogenic CDK12 alterations occur only as acquired, or somatic, mutations and suggest the gene could be considered for hereditary prostate cancer testing.
Current germline testing for hereditary prostate cancer focuses on genes such as BRCA1, BRCA2, and other DNA damage repair genes. Although CDK12 is routinely assessed on many somatic next-generation sequencing panels because of its therapeutic relevance, it is not currently included in standard germline testing panels.
Researchers analyzed germline sequencing data from 4,535 patients with aggressive prostate cancer enrolled in two independent cohorts in Canada and the United States. They identified five unrelated patients carrying inherited truncating CDK12 variants, representing approximately 0.1 percent of the study population. All five patients were diagnosed with high-grade metastatic prostate cancer between the ages of 44 and 62 years.
To determine whether the inherited variants contributed to tumor development, the investigators analyzed matched tumor samples. Each tumor harbored a second somatic CDK12 alteration together with the characteristic tandem duplication genomic instability signature associated with CDK12 loss, supporting a causal role for the inherited variants. In two patients, separate primary tumors acquired different secondary CDK12 alterations, providing additional evidence that CDK12 inactivation drove disease development.
"The tumors provided us with a genetic signature that pointed directly back to CDK12," said lead author Sofie Tolmeijer in a press release. "It gave us compelling evidence that these inherited mutations were playing a direct role in causing their cancer."
Although inherited CDK12 variants were rare, family histories revealed multiple cases of prostate cancer, and several families also included ovarian cancer. The researchers additionally identified a patient with ovarian cancer carrying an inherited CDK12 variant whose tumor showed the same characteristic molecular signature, suggesting the gene's role in hereditary cancer warrants further investigation.
The findings highlight a potential opportunity to expand molecular testing. Because CDK12 is already included on many tumor sequencing panels, identifying a pathogenic-appearing CDK12 alteration could prompt confirmatory germline testing and cascade testing of at-risk relatives. The investigators also recommend evaluating the addition of CDK12 to hereditary prostate cancer testing panels.
"One of the most exciting aspects of this discovery is that we already have the technology needed to act on it," said senior author Alexander Wyatt. "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 authors noted that larger prospective studies are needed to better define cancer risk, penetrance, and optimal screening strategies for CDK12 variant carriers before changes to clinical practice can be considered.
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