@article{dc767f64c8344b33a0fd0324e0adbbbc,
title = "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. Loss of both alleles of the CDK12 gene defines a molecular subtype of metastatic castration-resistant prostate cancer that is potentially targetable with immune checkpoint inhibitors.",
keywords = "CDK12, focal tandem duplications, gene fusions, immunotherapy, metastatic castration-resistant prostate cancer, neoantigens",
author = "{PCF/SU2C International Prostate Cancer Dream Team} and Wu, {Yi Mi} and Marcin Cie{\'s}lik and Lonigro, {Robert J.} and Pankaj Vats and Reimers, {Melissa A.} and Xuhong Cao and Yu Ning and Lisha Wang and Kunju, {Lakshmi P.} and {de Sarkar}, Navonil and Heath, {Elisabeth I.} and Jonathan Chou and Feng, {Felix Y.} and Nelson, {Peter S.} and {de Bono}, {Johann S.} and Weiping Zou and Bruce Montgomery and Ajjai Alva and Robinson, {Dan R.} and Chinnaiyan, {Arul M.}",
note = "Funding Information: We gratefully acknowledge all patients who participated. We thank Stephanie Ellison, Ph.D., for assistance in preparing this manuscript and Fuzon Chung for CDK12 knockdown in cell lines. We also acknowledge the efforts of the MI-Oncoseq team. This work was supported by the Prostate Cancer Foundation (PCF), StandUp2 Cancer (SU2C)-Prostate Cancer Foundation Prostate Dream Team (SU2C-AACR-DT0712), Department of Defense (DOD) (W81XWH-15-1-0562), Early Detection Research Network (U01 CA214170), and Prostate SPORE (P50 CA186786, P50 CA097186). M.C. is supported by a PCF Young Investigator Grant and a DOD Prostate Cancer Research Program Idea Development Award (PC160429). A.M.C. is a Howard Hughes Medical Institute Investigator, Taubman Scholar, and American Cancer Society Professor. Funding Information: We gratefully acknowledge all patients who participated. We thank Stephanie Ellison, Ph.D., for assistance in preparing this manuscript and Fuzon Chung for CDK12 knockdown in cell lines. We also acknowledge the efforts of the MI-Oncoseq team. This work was supported by the Prostate Cancer Foundation (PCF), StandUp2 Cancer (SU2C)-Prostate Cancer Foundation Prostate Dream Team ( SU2C-AACR-DT0712 ), Department of Defense (DOD) ( W81XWH-15-1-0562 ), Early Detection Research Network ( U01 CA214170 ), and Prostate SPORE ( P50 CA186786 , P50 CA097186 ). M.C. is supported by a PCF Young Investigator Grant and a DOD Prostate Cancer Research Program Idea Development Award ( PC160429 ). A.M.C. is a Howard Hughes Medical Institute Investigator, Taubman Scholar, and American Cancer Society Professor. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jun,
day = "14",
doi = "10.1016/j.cell.2018.04.034",
language = "English",
volume = "173",
pages = "1770--1782.e14",
journal = "Cell",
issn = "0092-8674",
number = "7",
}