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

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

doi:10.1016/j.cell.2018.04.034

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

Cell. 2018 Jun 14;173(7):1770-1782.e14. doi: 10.1016/j.cell.2018.04.034.

Authors

Yi-Mi Wu¹, Marcin Cieślik¹, Robert J Lonigro², Pankaj Vats², Melissa A Reimers³, Xuhong Cao², Yu Ning², Lisha Wang², Lakshmi P Kunju⁴, Navonil de Sarkar⁵, Elisabeth I Heath⁶, Jonathan Chou⁷, Felix Y Feng⁸, Peter S Nelson⁹, Johann S de Bono¹⁰, Weiping Zou¹¹, Bruce Montgomery¹², Ajjai Alva¹³; PCF/SU2C International Prostate Cancer Dream Team; Dan R Robinson¹⁴, Arul M Chinnaiyan¹⁵

Affiliations

¹ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
² Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ 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.
⁵ Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁶ 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.
⁷ Department of Medicine, University of California at San Francisco, San Francisco, CA 94143, USA.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² Department of Medicine, University of Washington, Seattle, WA 98109, USA; Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, WA 98109, USA.
¹³ 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.
¹⁴ 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: [email protected].
¹⁵ 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: [email protected].

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.

Keywords: CDK12; focal tandem duplications; gene fusions; immunotherapy; metastatic castration-resistant prostate cancer; neoantigens.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antibodies, Monoclonal / therapeutic use
Cell Line, Tumor
Chemokine CCL21 / genetics
Chemokine CCL21 / metabolism
Cyclin-Dependent Kinases / antagonists & inhibitors
Cyclin-Dependent Kinases / genetics
Cyclin-Dependent Kinases / metabolism*
DNA Repair
Gene Expression Regulation, Neoplastic
Genomic Instability
Humans
Male
Mutation, Missense
Neoplasm Staging
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Phenotype
Programmed Cell Death 1 Receptor / immunology
Prostate / diagnostic imaging
Prostatic Neoplasms / drug therapy
Prostatic Neoplasms / immunology
Prostatic Neoplasms / pathology*
RNA Interference
RNA, Small Interfering / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
T-Lymphocytes / metabolism
T-Lymphocytes / pathology
Tomography, X-Ray Computed

Substances

Antibodies, Monoclonal
Chemokine CCL21
Nuclear Proteins
Programmed Cell Death 1 Receptor
RNA, Small Interfering
Repressor Proteins
SPOP protein, human
CDK12 protein, human
Cyclin-Dependent Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding