Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer
Autor: | Wu, Yi-Mi, Cieślik, Marcin, Lonigro, Robert J, Vats, Pankaj, Reimers, Melissa A, Cao, Xuhong, Ning, Yu, Wang, Lisha, Kunju, Lakshmi P, de Sarkar, Navonil, Heath, Elisabeth I, Chou, Jonathan, Feng, Felix Y, Nelson, Peter S, de Bono, Johann S, Zou, Weiping, Montgomery, Bruce, Alva, Ajjai, PCF/SU2C International Prostate Cancer Dream Team, Robinson, Dan R, Chinnaiyan, Arul M |
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Rok vydání: | 2018 |
Předmět: |
Male
Urologic Diseases PCF/SU2C International Prostate Cancer Dream Team DNA Repair T-Lymphocytes Programmed Cell Death 1 Receptor Small Interfering Medical and Health Sciences Genomic Instability Antibodies gene fusions Cell Line focal tandem duplications Monoclonal Genetics Humans 2.1 Biological and endogenous factors Aetiology Tomography Neoplasm Staging Cancer Neoplastic Tumor Chemokine CCL21 Prostate Cancer Prostate Prostatic Neoplasms Nuclear Proteins Biological Sciences Cyclin-Dependent Kinases X-Ray Computed Repressor Proteins Phenotype Good Health and Well Being Gene Expression Regulation metastatic castration-resistant prostate cancer Mutation RNA RNA Interference immunotherapy Missense CDK12 neoantigens Biotechnology Developmental Biology |
Zdroj: | Cell, vol 173, iss 7 |
Popis: | 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 Tcell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy. |
Databáze: | OpenAIRE |
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