Cell
Volume 173, Issue 7, 14 June 2018, Pages 1770-1782.e14
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Article
Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer

https://doi.org/10.1016/j.cell.2018.04.034Get rights and content
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Highlights

  • CDK12 biallelic inactivating mutations define a distinct subtype of prostate cancer

  • CDK12 loss is associated with genomic instability and focal tandem duplications

  • CDK12 loss leads to increased gene fusions, neoantigen burden, and T cell infiltration

  • Patients with CDK12 mutant tumors may benefit from immune checkpoint inhibition

Summary

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

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

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These authors contributed equally

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