Cargando…
_version_ 1783426105359728640
author Abida, Wassim
Cyrta, Joanna
Heller, Glenn
Prandi, Davide
Armenia, Joshua
Coleman, Ilsa
Cieslik, Marcin
Benelli, Matteo
Robinson, Dan
Van Allen, Eliezer M.
Sboner, Andrea
Fedrizzi, Tarcisio
Mosquera, Juan Miguel
Robinson, Brian D.
De Sarkar, Navonil
Kunju, Lakshmi P.
Tomlins, Scott
Wu, Yi Mi
Nava Rodrigues, Daniel
Loda, Massimo
Gopalan, Anuradha
Reuter, Victor E.
Pritchard, Colin C.
Mateo, Joaquin
Bianchini, Diletta
Miranda, Susana
Carreira, Suzanne
Rescigno, Pasquale
Filipenko, Julie
Vinson, Jacob
Montgomery, Robert B.
Beltran, Himisha
Heath, Elisabeth I.
Scher, Howard I.
Kantoff, Philip W.
Taplin, Mary-Ellen
Schultz, Nikolaus
deBono, Johann S.
Demichelis, Francesca
Nelson, Peter S.
Rubin, Mark A.
Chinnaiyan, Arul M.
Sawyers, Charles L.
author_facet Abida, Wassim
Cyrta, Joanna
Heller, Glenn
Prandi, Davide
Armenia, Joshua
Coleman, Ilsa
Cieslik, Marcin
Benelli, Matteo
Robinson, Dan
Van Allen, Eliezer M.
Sboner, Andrea
Fedrizzi, Tarcisio
Mosquera, Juan Miguel
Robinson, Brian D.
De Sarkar, Navonil
Kunju, Lakshmi P.
Tomlins, Scott
Wu, Yi Mi
Nava Rodrigues, Daniel
Loda, Massimo
Gopalan, Anuradha
Reuter, Victor E.
Pritchard, Colin C.
Mateo, Joaquin
Bianchini, Diletta
Miranda, Susana
Carreira, Suzanne
Rescigno, Pasquale
Filipenko, Julie
Vinson, Jacob
Montgomery, Robert B.
Beltran, Himisha
Heath, Elisabeth I.
Scher, Howard I.
Kantoff, Philip W.
Taplin, Mary-Ellen
Schultz, Nikolaus
deBono, Johann S.
Demichelis, Francesca
Nelson, Peter S.
Rubin, Mark A.
Chinnaiyan, Arul M.
Sawyers, Charles L.
author_sort Abida, Wassim
collection PubMed
description Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
format Online
Article
Text
id pubmed-6561293
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-65612932019-06-17 Genomic correlates of clinical outcome in advanced prostate cancer Abida, Wassim Cyrta, Joanna Heller, Glenn Prandi, Davide Armenia, Joshua Coleman, Ilsa Cieslik, Marcin Benelli, Matteo Robinson, Dan Van Allen, Eliezer M. Sboner, Andrea Fedrizzi, Tarcisio Mosquera, Juan Miguel Robinson, Brian D. De Sarkar, Navonil Kunju, Lakshmi P. Tomlins, Scott Wu, Yi Mi Nava Rodrigues, Daniel Loda, Massimo Gopalan, Anuradha Reuter, Victor E. Pritchard, Colin C. Mateo, Joaquin Bianchini, Diletta Miranda, Susana Carreira, Suzanne Rescigno, Pasquale Filipenko, Julie Vinson, Jacob Montgomery, Robert B. Beltran, Himisha Heath, Elisabeth I. Scher, Howard I. Kantoff, Philip W. Taplin, Mary-Ellen Schultz, Nikolaus deBono, Johann S. Demichelis, Francesca Nelson, Peter S. Rubin, Mark A. Chinnaiyan, Arul M. Sawyers, Charles L. Proc Natl Acad Sci U S A PNAS Plus Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations. National Academy of Sciences 2019-06-04 2019-05-06 /pmc/articles/PMC6561293/ /pubmed/31061129 http://dx.doi.org/10.1073/pnas.1902651116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Abida, Wassim
Cyrta, Joanna
Heller, Glenn
Prandi, Davide
Armenia, Joshua
Coleman, Ilsa
Cieslik, Marcin
Benelli, Matteo
Robinson, Dan
Van Allen, Eliezer M.
Sboner, Andrea
Fedrizzi, Tarcisio
Mosquera, Juan Miguel
Robinson, Brian D.
De Sarkar, Navonil
Kunju, Lakshmi P.
Tomlins, Scott
Wu, Yi Mi
Nava Rodrigues, Daniel
Loda, Massimo
Gopalan, Anuradha
Reuter, Victor E.
Pritchard, Colin C.
Mateo, Joaquin
Bianchini, Diletta
Miranda, Susana
Carreira, Suzanne
Rescigno, Pasquale
Filipenko, Julie
Vinson, Jacob
Montgomery, Robert B.
Beltran, Himisha
Heath, Elisabeth I.
Scher, Howard I.
Kantoff, Philip W.
Taplin, Mary-Ellen
Schultz, Nikolaus
deBono, Johann S.
Demichelis, Francesca
Nelson, Peter S.
Rubin, Mark A.
Chinnaiyan, Arul M.
Sawyers, Charles L.
Genomic correlates of clinical outcome in advanced prostate cancer
title Genomic correlates of clinical outcome in advanced prostate cancer
title_full Genomic correlates of clinical outcome in advanced prostate cancer
title_fullStr Genomic correlates of clinical outcome in advanced prostate cancer
title_full_unstemmed Genomic correlates of clinical outcome in advanced prostate cancer
title_short Genomic correlates of clinical outcome in advanced prostate cancer
title_sort genomic correlates of clinical outcome in advanced prostate cancer
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561293/
https://www.ncbi.nlm.nih.gov/pubmed/31061129
http://dx.doi.org/10.1073/pnas.1902651116
work_keys_str_mv AT abidawassim genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT cyrtajoanna genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT hellerglenn genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT prandidavide genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT armeniajoshua genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT colemanilsa genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT cieslikmarcin genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT benellimatteo genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT robinsondan genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT vanalleneliezerm genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT sbonerandrea genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT fedrizzitarcisio genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT mosquerajuanmiguel genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT robinsonbriand genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT desarkarnavonil genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT kunjulakshmip genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT tomlinsscott genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT wuyimi genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT navarodriguesdaniel genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT lodamassimo genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT gopalananuradha genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT reutervictore genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT pritchardcolinc genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT mateojoaquin genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT bianchinidiletta genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT mirandasusana genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT carreirasuzanne genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT rescignopasquale genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT filipenkojulie genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT vinsonjacob genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT montgomeryrobertb genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT beltranhimisha genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT heathelisabethi genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT scherhowardi genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT kantoffphilipw genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT taplinmaryellen genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT schultznikolaus genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT debonojohanns genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT demichelisfrancesca genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT nelsonpeters genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT rubinmarka genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT chinnaiyanarulm genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer
AT sawyerscharlesl genomiccorrelatesofclinicaloutcomeinadvancedprostatecancer