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

Cell. 2018 Jun 14;173(7):1770-1782.e14. doi: 10.1016/j.cell.2018.04.034.

Abstract

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.

Keywords: CDK12; focal tandem duplications; gene fusions; immunotherapy; metastatic castration-resistant prostate cancer; neoantigens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal / therapeutic use
  • Cell Line, Tumor
  • Chemokine CCL21 / genetics
  • Chemokine CCL21 / metabolism
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • DNA Repair
  • Gene Expression Regulation, Neoplastic
  • Genomic Instability
  • Humans
  • Male
  • Mutation, Missense
  • Neoplasm Staging
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phenotype
  • Programmed Cell Death 1 Receptor / immunology
  • Prostate / diagnostic imaging
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / pathology*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Tomography, X-Ray Computed

Substances

  • Antibodies, Monoclonal
  • Chemokine CCL21
  • Nuclear Proteins
  • Programmed Cell Death 1 Receptor
  • RNA, Small Interfering
  • Repressor Proteins
  • SPOP protein, human
  • CDK12 protein, human
  • Cyclin-Dependent Kinases