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Daniel Nava Rodrigues, … , Eliezer M. Van Allen, Johann S. de Bono
Published September 4, 2018
Citation Information: J Clin Invest. 2018;128(10):4441-4453. https://doi.org/10.1172/JCI121924.
Citation Information: J Clin Invest. 2018;128(10):4441-4453. https://doi.org/10.1172/JCI121924.
Abstract
BACKGROUND. Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection. METHODS. Defective mismatch repair (dMMR) status was determined by either loss of mismatch repair protein expression on IHC or microsatellite instability (MSI) by PCR in 127 APC biopsies from 124 patients (Royal Marsden [RMH] cohort); MSI by targeted panel next-generation sequencing (MSINGS) was then evaluated in the same cohort and in 254 APC samples from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF). Whole exome sequencing (WES) data from this latter cohort were analyzed for pathogenic MMR gene variants, mutational load, and mutational signatures. Transcriptomic data, available for 168 samples, was also performed. RESULTS. Overall, 8.1% of patients in the RMH cohort had some evidence of dMMR, which associated with decreased overall survival. Higher MSINGS scores associated with dMMR, and these APCs were enriched for higher T cell infiltration and PD-L1 protein expression. Exome MSINGS scores strongly correlated with targeted panel MSINGS scores (r = 0.73, P < 0.0001), and higher MSINGS scores associated with dMMR mutational signatures in APC exomes. dMMR mutational signatures also associated with MMR gene mutations and increased immune cell, immune checkpoint, and T cell–associated transcripts. APC with dMMR mutational signatures overexpressed a variety of immune transcripts, including CD200R1, BTLA, PD-L1, PD-L2, ADORA2A, PIK3CG, and TIGIT. CONCLUSION. These data could impact immune target selection, combination therapeutic strategy selection, and selection of predictive biomarkers for immunotherapy in APC. FUNDING. We acknowledge funding support from Movember, Prostate Cancer UK, The Prostate Cancer Foundation, SU2C, and Cancer Research UK.
Authors
Daniel Nava Rodrigues, Pasquale Rescigno, David Liu, Wei Yuan, Suzanne Carreira, Maryou B. Lambros, George Seed, Joaquin Mateo, Ruth Riisnaes, Stephanie Mullane, Claire Margolis, Diana Miao, Susana Miranda, David Dolling, Matthew Clarke, Claudia Bertan, Mateus Crespo, Gunther Boysen, Ana Ferreira, Adam Sharp, Ines Figueiredo, Daniel Keliher, Saud Aldubayan, Kelly P. Burke, Semini Sumanasuriya, Mariane Sousa Fontes, Diletta Bianchini, Zafeiris Zafeiriou, Larissa Sena Teixeira Mendes, Kent Mouw, Michael T. Schweizer, Colin C. Pritchard, Stephen Salipante, Mary-Ellen Taplin, Himisha Beltran, Mark A. Rubin, Marcin Cieslik, Dan Robinson, Elizabeth Heath, Nikolaus Schultz, Joshua Armenia, Wassim Abida, Howard Scher, Christopher Lord, Alan D’Andrea, Charles L. Sawyers, Arul M. Chinnaiyan, Andrea Alimonti, Peter S. Nelson, Charles G. Drake, Eliezer M. Van Allen, Johann S. de Bono
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Schepisi G, Brighi N, Cursano MC, Gurioli G, Ravaglia G, Altavilla A, Burgio SL, Testoni S, Menna C, Farolfi A, Casadei C, Tonini G, Santini D, De Giorgi U |
Journal of Oncology | 2019 |
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Molecular Characterization and Clinical Outcomes of Primary Gleason Pattern 5 Prostate Cancer After Radical Prostatectomy.
Velho PI, Lim D, Wang H, Park JC, Kaur HB, Almutairi F, Carducci MA, Denmeade SR, Markowski MC, Isaacs WB, Antonarakis ES, Pritchard CC, Eisenberger MA, Lotan TL |
JCO Precision Oncology | 2019 |
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Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer.
Di Mitri D, Mirenda M, Vasilevska J, Calcinotto A, Delaleu N, Revandkar A, Gil V, Boysen G, Losa M, Mosole S, Pasquini E, D'Antuono R, Masetti M, Zagato E, Chiorino G, Ostano P, Rinaldi A, Gnetti L, Graupera M, Martins Figueiredo Fonseca AR, Pereira Mestre R, Waugh D, Barry S, De Bono J, Alimonti A |
Cell Reports | 2019 |
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The PD-1/PD-L1 pathway in advanced prostate cancer-have we milked this cow?
Picardo SL, Hansen AR |
Annals of translational medicine | 2019 |
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A New Molecular Taxonomy to Predict Immune Checkpoint Inhibitor Sensitivity in Prostate Cancer.
Antonarakis ES |
The oncologist | 2019 |
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Genomic Alteration Burden in Advanced Prostate Cancer and Therapeutic Implications.
Ryan MJ, Bose R |
Frontiers in Oncology | 2019 |
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Heritability and genome-wide association study of benign prostatic hyperplasia (BPH) in the eMERGE network
Hellwege JN, Stallings S, Torstenson ES, Carroll R, Borthwick KM, Brilliant MH, Crosslin D, Gordon A, Hripcsak G, Jarvik GP, Linneman JG, Devi P, Peissig PL, Sleiman PA, Hakonarson H, Ritchie MD, Verma SS, Shang N, Denny JC, Roden DM, Velez Edwards DR, Edwards TL |
Scientific Reports | 2019 |
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Darolutamide For Castration-Resistant Prostate Cancer
Bastos DA, Antonarakis ES |
OncoTargets and therapy | 2019 |
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Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2009 |
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