CDK12

Overview

CDK12 is a cyclin-dependent kinase that regulates transcriptional elongation and the DNA damage response (DDR) by phosphorylating RNA Pol II. Biallelic loss of CDK12 in prostate cancer produces focal tandem duplications across the genome and a distinctive mutational signature, defining a molecularly distinct subtype associated with neoantigens and potentially immune checkpoint sensitivity. CDK12-mutant prostate cancer is considered a biomarker for immunotherapy response investigation.

Alterations observed in the corpus

  • Biallelic loss via dual mutations or structural variation in 4 of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) series; associated with CDK12-loss-specific focal copy-number gains PMID:38488813.
  • CDK12 SNVs used to assign patients to the tandem-duplicator-enriched genomic subtype in a 444-patient HGSOC multimodal risk-stratification study; CDK12-subtype assignment took precedence over HRD-DDR variant evidence per the MSKCC subtype rules PMID:35764743.
  • CDK12 alterations identified as recurrent post-treatment changes and associated with Gleason score and metastasis patterns in PRAD in the MSK-CHORD real-world cohort (n=42,655 patients) PMID:39506116.
  • Mutations associated with tandem duplicator (TD) phenotype in HGSOC PMID:36517593
  • CDK12 structural variants in 3 GBC patients including fusions (OncoKB level 3B) PMID:36228155
  • Identified as somatically mutated in HGSOC in TCGA integrated genomic analysis of ovarian carcinoma PMID:21720365
  • CDK12 mutations identified in prostate cancer WES of 112 tumors (Michigan cohort), implicating DNA damage response and transcription regulation PMID:22722839
  • Tumor-suppressor mutation detected in prostate cancer cell lines derived from CRPC PMID:25201530
  • DNA-repair pathway alteration in mCRPC; part of 22.7% broader DNA-repair alteration aggregate including BRCA2, BRCA1, ATM, FANCA, RAD51B, RAD51C, and BRIP1 PMID:26000489
  • Loss-of-function or homozygous deletion in 1% (4 tumors) in primary prostate cancer; CDK12 loss contributes to the 19% DNA-repair-gene-defect prevalence supporting PARP-inhibitor candidacy PMID:26544944
  • Somatic CDK12 loss identified as a candidate HR-pathway alteration in prostate cancer across locoregional, metastatic noncastrate, and mCRPC disease states; CDK12 loss hypothesized to confer PARP inhibitor sensitivity based on preclinical evidence PMID:28825054.
  • CDK12 is a significantly mutated gene (SMG) in prostate cancer with a truncating-biased mutation pattern (p<0.001) and frequent biallelic inactivation (15/31 in discovery cohort, 27/56 in MSK-IMPACT validation); missense variants cluster in the kinase domain; frequent biallelic CDK12 loss is consistent with a therapeutically relevant DNA-repair phenotype in metastatic prostate cancer PMID:29610475.

Cancer types (linked)

  • PRAD/PRNE: CDK12 biallelic inactivation identified in patient-derived xenograft models; associated with focal tandem duplications and DDR pathway dysregulation; predominantly observed in adenocarcinoma models PMID:38488813.
  • HGSOC: CDK12 SNVs define the tandem-duplicator genomic subtype used in a multimodal ML risk-stratification model; subtype assignment overrides concurrent HRD-DDR evidence PMID:35764743.

Co-occurrence and mutual exclusivity

  • CDK12 loss was observed predominantly in adenocarcinoma PDX models; DDR pathway gene driver alterations (CDK12, ATM, BRCA1/2, CHEK2) were enriched in adenocarcinoma vs. NEPC models PMID:38488813.

Therapeutic relevance

  • CDK12 biallelic loss generates a neoantigen-rich mutational landscape that may sensitize tumors to immune checkpoint inhibitors; this has been a rationale for ongoing clinical trials of pembrolizumab in CDK12-mutant mCRPC PMID:38488813.

Open questions

  • CDK12-loss-associated focal copy-number gains observed in PDXs require further characterization to identify the oncogenic drivers amplified at these loci.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:36517593

This page was processed by crosslinker on 2026-05-14. - PMID:36228155

This page was processed by crosslinker on 2026-05-14. - PMID:21720365

This page was processed by crosslinker on 2026-05-14. - PMID:22722839

This page was processed by crosslinker on 2026-05-14. - PMID:25201530

This page was processed by crosslinker on 2026-05-14. - PMID:26000489

This page was processed by crosslinker on 2026-05-14. - PMID:26544944

This page was processed by wiki-cli on 2026-05-14. - PMID:28825054

This page was processed by wiki-cli on 2026-05-15. - PMID:29610475

This page was processed by wiki-cli on 2026-05-15.