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

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

Cell

journal_title

Cell

authors

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.,Robins

doi

10.1016/j.cell.2018.04.034

subject

Has Abstract

pub_date

2018-06-14 00:00:00

pages

1770-1782.e14

issue

7

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(18)30565-8

journal_volume

173

pub_type

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