Journal
CELL
Volume 173, Issue 7, Pages 1770-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.04.034
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Funding
- Prostate Cancer Foundation (PCF)
- StandUp2 Cancer (SU2C)-Prostate Cancer Foundation Prostate Dream Team [SU2C-AACR-DT0712]
- Department of Defense (DOD) [W81XWH-15-1-0562]
- Early Detection Research Network [U01 CA214170]
- Prostate SPORE [P50 CA186786, P50 CA097186]
- PCF Young Investigator Grant
- DOD Prostate Cancer Research Program Idea Development Award [PC160429]
- CDMRP [PC160429, 917690] Funding Source: Federal RePORTER
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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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