BRCA2, ATM, and CDK12 defects differentially shape prostate tumor driver genomics and clinical aggression

DNA damage repair (DDR) defects are common across cancer types and indicate vulnerability to targeted therapies. In prostate cancer there is an urgent need for practical DDR defect detection strategies and resolution of associated clinicogenomic features. Here, we profiled circulating tumor DNA (ctDNA) from metastatic prostate cancer patients and identified BRCA2, ATM, and CDK12 as the most frequently disrupted DDR genes. CtDNA analysis distinguished monoallelic from biallelic defects and revealed mechanistic heterogeneity underlying biallelic inactivation. BRCA2-deficient samples exhibited frequent disruption of tumor suppressors via chromosomal rearrangements, while CDK12 mutations were instead associated with oncogene amplification. ATM-mutation appeared mutually exclusive with TP53 mutation. Loss of BRCA2 and CDK12—but not ATM—was associated with inferior clinical outcomes compared to DDR-intact disease. Our results suggest that distinct DDR aberrations differentially shape tumor genomics and clinical aggression. The ease of DDR-defect characterization in ctDNA suggests that blood-based assays can help identify patients suitable for exploitative therapies.EGA study EGAS00001004800