Germline CDK12 variants in aggressive prostate cancer
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.
Authors
- Kim N. Chi (ORCID: https://orcid.org/0000-0002-3782-7226)
- Kim van der Zande
- Corinne Maurice‐Dror (ORCID: https://orcid.org/0000-0003-4455-4497)
- Wilbert Zwart (ORCID: https://orcid.org/0000-0002-9823-7289)
- Sofie H. Tolmeijer (ORCID: https://orcid.org/0000-0003-4066-885X)
- Kasmintan A. Schrader (ORCID: https://orcid.org/0000-0002-7413-4314)
- Andries M. Bergman (ORCID: https://orcid.org/0000-0001-5223-2549)
- Catherine Wang
- Niven Mehra (ORCID: https://orcid.org/0000-0002-4794-1831)
- Claire M. de la Calle (ORCID: https://orcid.org/0000-0003-1770-7953)
- Gavin Ha (ORCID: https://orcid.org/0000-0001-7578-7272)
- Nielka P. van Erp (ORCID: https://orcid.org/0000-0003-1553-178X)
- Lesley Seymour (ORCID: https://orcid.org/0000-0001-8081-0799)
- Heather H. Cheng (ORCID: https://orcid.org/0000-0002-1365-0702)
- Lílian Córdova
- Peter C. Black (ORCID: https://orcid.org/0000-0002-2919-7068)
- Alexander W. Wyatt (ORCID: https://orcid.org/0000-0003-2399-0329)
- Vahid Akbari (ORCID: https://orcid.org/0000-0001-8005-7776)
- Peter M. Lansdorp (ORCID: https://orcid.org/0000-0001-7435-1071)
- Andrew J. Murtha (ORCID: https://orcid.org/0000-0003-3980-7656)
- Michael S. Hofman (ORCID: https://orcid.org/0000-0001-8622-159X)
- Shahneen Kaur Sandhu (ORCID: https://orcid.org/0000-0002-8660-4475)
- Colin C. Pritchard (ORCID: https://orcid.org/0000-0002-2461-1557)
- Ian D. Davis (ORCID: https://orcid.org/0000-0002-9066-8244)
- Peter S. Nelson (ORCID: https://orcid.org/0000-0002-5451-5726)
- David Olmos (ORCID: https://orcid.org/0000-0002-7003-4826)
- Arun Azad (ORCID: https://orcid.org/0000-0001-7350-5622)
- Elena Castro (ORCID: https://orcid.org/0000-0002-3691-6454)
- Piet Ost (ORCID: https://orcid.org/0000-0002-2203-4848)
- Christian Kollmannsberger (ORCID: https://orcid.org/0000-0002-6329-761X)
- Gráinne Donnellan (ORCID: https://orcid.org/0009-0002-7373-7567)
- Mohamed Adil (ORCID: https://orcid.org/0000-0003-1787-644X)
- Steven J.M. Jones (ORCID: https://orcid.org/0000-0003-3394-2208)
Institutions
- HOGENT University of Applied Sciences and Arts (BE)
- BC Cancer Agency (CA)
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- Box Hill Hospital (AU)
- University of British Columbia (CA)
- Radboud University Nijmegen (NL)
- University of Washington (US)
- Queen's University (CA)
- Dutch Cancer Society (NL)
- Peter MacCallum Cancer Centre (AU)
- Ghent University Hospital (BE)
- Spinal Cord Injury BC (CA)
- Radboud University Medical Center (NL)
- Ghent University (BE)
- Fred Hutch Cancer Center (US)
- Terry Fox Research Institute (CA)
- Hospital Universitario 12 De Octubre (ES)
- DC Cancer Consortium (US)
- Oncode Institute (NL)
- BC Cancer Foundation (CA)
- Canada's Michael Smith Genome Sciences Centre (CA)
- Monash University (AU)
- Seattle University (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-07-02
- DOI
- https://doi.org/10.1158/2159-8290.cd-26-0084
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00