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

PCF/SU2C International Prostate Cancer Dream Team

Research output: Contribution to journalArticle

137 Scopus citations

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. Loss of both alleles of the CDK12 gene defines a molecular subtype of metastatic castration-resistant prostate cancer that is potentially targetable with immune checkpoint inhibitors.

Original languageEnglish
Pages (from-to)1770-1782.e14
JournalCell
Volume173
Issue number7
DOIs
StatePublished - Jun 14 2018
Externally publishedYes

Keywords

  • CDK12
  • focal tandem duplications
  • gene fusions
  • immunotherapy
  • metastatic castration-resistant prostate cancer
  • neoantigens

Fingerprint Dive into the research topics of 'Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer'. Together they form a unique fingerprint.

  • Cite this