Predicted Immunogenicity of CDK12 Biallelic Loss-of-Function Tumors Varies across Cancer Types

CDK12 biallelic inactivation is associated with a distinct genomic signature of focal tandem duplications (FTDs). Gene fusions resulting from FTDs increase neoantigen load, raising interest in CDK12 as a biomarker of response to immune checkpoint inhibitors. Despite evidence of FTDs in multiple CDK12-altered cancer types, notably prostate and ovarian, report of fusion-associated neoantigen load is limited to prostate cancer. Molecular profiles were retrospectively reviewed for CDK12-biallelic (CDK12-biLOF) and -monoallelic loss-of-function (CDK12-monoLOF) in a primary cohort of >9000 tumors, representing 39 cancer types, and immune epitopes were predicted from fusions detected by whole transcriptome sequencing. CDK12-biLOF was identified for 0.3% tumors overall, most frequently in prostate cancer (4.7%). CDK12-biLOF tumors had higher mean fusion rates and fusion-associated neoantigen load than CDK12-monoLOF and CDK12-WT tumors (P < 0.01). However, concurrent mismatch repair deficiency/microsatellite instability with CDK12-biLOF associated with low fusion rates. Among CDK12-biLOF tumors, fusion-associated neoantigen load was highest in prostate and ovarian cancers, which correlated with distinct immune profiles. In a validation cohort, CDK12-biLOF tumors (0.4%) exhibited high mean fusion rates, particularly for prostate and ovarian tumors. Low fusion rates in other CDK12-biLOF tumor types warrant further investigation and highlight the value of quantitative biomarkers. Fusion rate and fusion-associated neoantigen load are linked to CDK12-biLOF in select cancers and may help to identify responders of immune checkpoint inhibitor therapy.