Reference Detail

Ref Type

Journal Article

PMID

(29906450)

Authors

Wu YM, Cieślik M, Lonigro RJ, Vats P, Reimers MA, Cao X, Ning Y, Wang L, Kunju LP, de Sarkar N, Heath EI, Chou J, Feng FY, Nelson PS, de Bono JS, Zou W, Montgomery B, Alva A, null null, Robinson DR, Chinnaiyan AM

Title

Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell	173	7	2018 Jun 14	1770-1782.e14	Cell

URL

Abstract Text

Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12 mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12 mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
CDK12	NCBI	CRK7\|CRKR\|CRKRS		CDK12, cyclin dependent kinase 12, is a key regulator of transcription elongation, regulates the expression of genes involved in DNA repair, and is required for the maintenance of genomic stability (PMID: 24554720; PMID: 22012619). Loss and/or inactivation of CDK12 has been commonly observed in many solid tumor types, including prostate (PMID: 29906450, PMID: 31640893), breast, ovarian, endometrial, uterine (PMID: 30104286), and is a likely tumor suppressor (PMID: 30319007).	Tumor suppressor

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
CDK12	G923V	missense	unknown	CDK12 G923V lies within the protein kinase domain of the Cdk12 protein (PMID: 22512864). G923V has been identified in sequencing studies (PMID: 29906450, PMID: 32997692), but has not been biochemically characterized and therefore, its effect on Cdk12 protein function is unknown (PubMed, Oct 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CDK12 mutant	prostate cancer	predicted - sensitive	unspecified PD-1 antibody	Case Reports/Case Series	Actionable	In a clinical study, 50% (2/4) of prostate cancer patients with mutant CDK12 responded to an unspecified checkpoint inhibitor immunotherapy and had a corresponding decrease in prostate specific antigen (PMID: 29906450).	29906450