CDK12 mutations occur in 2-7% of metastatic prostate cancers (mPCa) and are considered to be exclusively somatic. Here, we identified five patients with mPCa (ages 44-62) harboring germline CDK12 truncating variants among 4,535 tested (0. 1%). All had CDK12-driven cancers defined by an additional somatic CDK12 variant and the CDK12-specific hallmark genomic instability signature characterized by hundreds of tandem duplications. Two patients had multiple independent CDK12-driven tumors with distinct secondary somatic CDK12 variants. Germline CDK12 truncating variants were enriched in mPCa compared to gnomAD V4.1.0 controls (n=807,162; odds ratio 11.4, 95% CI 3.6-27.8) and V2.1.1 non-cancer controls (n=134,187; odds ratio 29.6; 95% CI 6.8-28.6). Family history revealed multiple related individuals with prostate or ovarian cancer, and germline variant inheritance was confirmed in the two tested pedigrees. Our data suggest that germline CDK12 truncating variants are a rare driver of lethal mPCa.
Cancer discovery. 2026 Jul 02 [Epub ahead of print]
Sofie H Tolmeijer, Corinne Maurice-Dror, Shahneen Sandhu, Claire M de la Calle, Christian Kollmannsberger, Mohamed Adil, Catherine K Wang, Andrew J Murtha, Gráinne Donnellan, Nielka P van Erp, Niven Mehra, Michael S Hofman, Arun A Azad, Ian D Davis, Andries M Bergman, Wilbert Zwart, Kim van der Zande, Lesley Seymour, Peter C Black, Vahid Akbari, Lilian Cordova, Peter M Lansdorp, Steven Jm Jones, Peter S Nelson, Elena Castro, Kasmintan A Schrader, Gavin Ha, Heather H Cheng, Piet Ost, David Olmos, Kim N Chi, Colin C Pritchard, Alexander W Wyatt
University of British Columbia Vancouver, British Columbia Canada., BC Cancer-Vancouver, Vancouver, BC, Canada Vancouver, British Columbia Canada., Peter MacCallum Cancer Centre Melbourne, Victoria Australia., University of Washington Seattle United States., BC Cancer Agency Vancouver, British Columbia Canada., Fred Hutch Cancer Center United States., University of British Columbia Vancouver, BC Canada., Radboud University Medical Center Nijmegen Netherlands., Peter MacCallum Cancer Centre Melbourne, VIC Australia., Peter MacCallum Cancer Centre Melbourne Australia., Monash University Box Hill, Victoria Australia., The Netherlands Cancer Institute Amsterdam Netherlands., Queen's University Kingston, Ontario Canada., BC Cancer Agency Canada., University of British Columbia Canada., Terry Fox Foundation Vancouver, BC Canada., Canada's Michael Smith Genome Sciences Centre Vancouver, British Columbia Canada., Fred Hutch Cancer Center Seattle, WA United States., Hospital Universitario 12 De Octubre Madrid Spain., Fred Hutch Cancer Center Seattle United States., Cancer Consortium United States., Ghent University Gent Belgium., Hospital Universitario 12 De Octubre Madrid, Madrid Spain., BC Cancer Foundation Vancouver, British Columbia Canada., University of Washington Seattle, WA United States.