FCCC LOGO Faculty Publications
Elliott A , Zhang J , Zhang Q , Swensen J , Martin D , Xiu J , Geynisman DM , Vaena D , Herzog TJ , Holloway RW , El-Deiry WS , Spetzler D , Heath E , Stafford P , Korn WM
Predicted immunogenicity of CDK12 biallelic loss-of-function tumors varies across cancer types
J Mol Diagn. 2021 Sep 22
PMID: 34562615   
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Abstract
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 (ICIs). Despite evidence of FTDs in multiple CDK12-altered cancer types, notably for 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 >9,000 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 (n=29), most frequently in prostate cancer (4.7%, n=11). CDK12-biLOF tumors had higher mean fusion rates and fusion-associated neoantigen load than CDK12-monoLOF (P<0.01) and CDK12-WT tumors (P<0.001). 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%, n=47) exhibited high mean fusion rates, particularly for prostate and ovarian tumors. Low fusion rates in other CDK12-biLOF tumor types warrants further investigation and highlights 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 ICI therapy.
Notes
1943-7811 Elliott, Andrew Zhang, Jian Zhang, Qing Swensen, Jeffrey Martin, Daniel Xiu, Joanne Geynisman, Daniel M Vaena, Daniel Herzog, Thomas J Holloway, Robert W El-Deiry, Wafik S Spetzler, David Heath, Elisabeth Stafford, Phillip Korn, W Michael Journal Article United States J Mol Diagn. 2021 Sep 22:S1525-1578(21)00289-0. doi: 10.1016/j.jmoldx.2021.08.010.