UBC researchers find inherited CDK12 variants in five of 4,535 men with metastatic prostate cancer

Researchers at the University of British Columbia and partner centers report in Cancer Discovery that CDK12 variants can be inherited, not only acquired in the tumor. Among 4,535 patients with metastatic prostate cancer who were tested, five carried germline CDK12 truncating variants (0.1%). The patients were aged 44 to 62 aacrjournals.orgCancer Discoveryaacrjournals.orgOpen source ↗.

What the genetic data show

CDK12 mutations occur in 2% to 7% of metastatic prostate cancers and were considered exclusively somatic. All five patients had CDK12-driven cancers. Besides the germline variant, each tumor carried an additional somatic CDK12 variant and the CDK12-specific genomic instability signature, which consists of hundreds of tandem duplications.

Two patients had several independent CDK12-driven tumors, each with a distinct secondary somatic CDK12 variant. The authors consider these independent "second-hit" events and the characteristic signature as support for a causal role of the germline variant.

Germline CDK12 truncating variants were enriched in metastatic prostate cancer compared with controls. Against gnomAD v4.1.0 (n = 807,162) the odds ratio was 11.4 (95% CI, 3.6–27.8). Against gnomAD v2.1.1 noncancer controls (n = 134,187) it was 29.6 aacrjournals.orgCancer Discoveryaacrjournals.orgOpen source ↗.

Families and testing

Family history revealed multiple related individuals with prostate or ovarian cancer. Inheritance of the variant was confirmed in the two pedigrees that were tested. The authors conclude that germline CDK12 truncating variants are a rare driver of lethal metastatic prostate cancer and propose including CDK12 in hereditary cancer testing and risk stratification.

Lead author Sofie Tolmeijer said the tumors provided a genetic signature that pointed back to CDK12. Senior author Alexander Wyatt noted that every patient identified with the inherited variant already had metastatic disease at diagnosis.

The researchers also identified one more person with ovarian cancer who carried an inherited CDK12 variant. That tumor showed the same characteristic genetic changes. According to the authors, further research is needed to establish whether the variant increases ovarian cancer risk. They also state that CDK12 variants can already be detected with existing clinical technology.