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.
journal_name
Celljournal_title
Cellauthors
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,PCF\/SU2C International Prostate Cancer Dream Team.,Robinsdoi
10.1016/j.cell.2018.04.034subject
Has Abstractpub_date
2018-06-14 00:00:00pages
1770-1782.e14issue
7eissn
0092-8674issn
1097-4172pii
S0092-8674(18)30565-8journal_volume
173pub_type
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