Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics

CDK12 genomic alterations occur in several tumor types, but little is known about their oncogenic role and clinical significance.To describe the landscape of CDK12 alterations across solid cancers and the clinical features of CDK12-altered prostate cancer.A single-center retrospective study of 26743 patients across 25 solid tumor types who underwent tumor sequencing was performed. Clinicopathologic features and outcomes were assessed in prostate cancer.CDK12 alterations and their association with genomic characteristics are described. For prostate cancer patients, overall survival and time to castration resistance were assessed using univariable and multivariable Cox regression analysis.CDK12 alterations were identified in 404/26743 patients (1.5%) overall, but were most frequent in prostate (100/1875, 5.3%) and ovarian cancer (43/1034, 4.2%), in which they were associated with a high prevalence of truncating variants and biallelic inactivation. CDK12 alterations defined a genomic subtype of prostate cancer with a unique copy-number alteration profile and involvement of distinct oncogenic pathway alterations, including cell-cycle pathway genes. CDK12-altered prostate cancer was associated with somewhat more aggressive clinical features and shorter overall survival (median 64.4 vs 74.9 mo; p=0.032) independent of standard clinical factors and tumor copy-number alteration burden (adjusted hazard ratio 1.80, 95% confidence interval 1.12-2.89; p=0.024). The study is limited by its retrospective nature.CDK12 alteration is a rare event across solid cancers but defines a clinically distinct molecular subtype of prostate cancer associated with unique genomic alterations and slightly more aggressive clinical features.CDK12 gene alterations occur rarely across tumor types, but more frequently in prostate cancer, where they are associated with genomic instability, cell-cycle pathway gene alterations, and somewhat worse clinical outcomes, warranting further investigation of therapeutic targeting of this disease subset.