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Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 2018 Jun 14;173(7):1770-1782.e14

Date

06/16/2018

Pubmed ID

29906450

Pubmed Central ID

PMC6084431

DOI

10.1016/j.cell.2018.04.034

Scopus ID

2-s2.0-85047481697 (requires institutional sign-in at Scopus site)   376 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.

Author List

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, Robinson DR, Chinnaiyan AM

Author

Navonil De Sarkar PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Antibodies, Monoclonal
Cell Line, Tumor
Chemokine CCL21
Cyclin-Dependent Kinases
DNA Repair
Gene Expression Regulation, Neoplastic
Genomic Instability
Humans
Male
Mutation, Missense
Neoplasm Staging
Nuclear Proteins
Phenotype
Programmed Cell Death 1 Receptor
Prostate
Prostatic Neoplasms
RNA Interference
RNA, Small Interfering
Repressor Proteins
T-Lymphocytes
Tomography, X-Ray Computed