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

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.

Cell. 2018 Jun 14 [Epub]

Yi-Mi Wu, Marcin Cieślik, Robert J Lonigro, Pankaj Vats, Melissa A Reimers, Xuhong Cao, Yu Ning, Lisha Wang, Lakshmi P Kunju, Navonil de Sarkar, Elisabeth I Heath, Jonathan Chou, Felix Y Feng, Peter S Nelson, Johann S de Bono, Weiping Zou, Bruce Montgomery, Ajjai Alva, PCF/SU2C International Prostate Cancer Dream Team , Dan R Robinson, Arul M Chinnaiyan

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA., Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA., Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA., Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA., Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA., Department of Medicine, University of California at San Francisco, San Francisco, CA 94143, USA., Department of Medicine, University of California at San Francisco, San Francisco, CA 94143, USA; Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA 94143, USA; Department of Urology, University of California at San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143, USA., Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Cancer Biomarkers Team, Division of Clinical Studies, The Institute of Cancer Research, London SM2 5NG, UK; Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London SM2 5NG, UK., Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA., Department of Medicine, University of Washington, Seattle, WA 98109, USA; Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, WA 98109, USA., Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA., Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: ., Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: .

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