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

Area of Science:

• Genomics
• Cancer Biology
• Immunology

Background:

• CDK12 biallelic inactivation (CDK12-biLOF) is linked to focal tandem duplications (FTDs), which can increase neoantigen load.
• This suggests CDK12's potential as a biomarker for immune checkpoint inhibitor (ICI) response.
• Previous studies primarily focused on prostate cancer's fusion-associated neoantigen load.

Purpose of the Study:

• To investigate the prevalence and genomic consequences of CDK12-biLOF across diverse cancer types.
• To assess the correlation between CDK12-biLOF, gene fusion rates, and neoantigen load.
• To explore the potential of CDK12-biLOF as a predictive biomarker for ICI therapy.

Main Methods:

• Retrospective analysis of molecular profiles from over 9000 tumors across 39 cancer types.
• Identification of CDK12-biallelic and -monoallelic loss-of-function (CDK12-monoLOF) alterations.
• Whole transcriptome sequencing to detect gene fusions and predict immune epitopes.

Main Results:

• CDK12-biLOF was found in 0.3% of tumors, most common in prostate cancer (4.7%).
• CDK12-biLOF tumors exhibited significantly higher fusion rates and neoantigen load compared to CDK12-monoLOF and wild-type tumors.
• Prostate and ovarian cancers with CDK12-biLOF showed the highest fusion-associated neoantigen load, correlating with distinct immune profiles.

Conclusions:

• CDK12-biLOF is associated with increased fusion rates and neoantigen load in specific cancers, notably prostate and ovarian.
• Concurrent mismatch repair deficiency/microsatellite instability with CDK12-biLOF may reduce fusion rates, requiring further study.
• Quantitative assessment of fusion rate and neoantigen load in CDK12-biLOF tumors could aid in identifying potential responders to immune checkpoint inhibitor therapy.