Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer.

Adaptor Proteins, Vesicular Transport Androgen Antagonists / therapeutic use Antineoplastic Agents, Hormonal / therapeutic use Antineoplastic Combined Chemotherapy Protocols / pharmacology Humans Male Neoadjuvant Therapy / methods Nuclear Proteins / drug effects Prostate-Specific Antigen / drug effects Prostatectomy / methods Prostatic Neoplasms / drug therapy Repressor Proteins / drug effects Risk
AR PTEN RNA-seq SPOP SPOPL TGF-β TP53 neoadjuvant androgen pathway inhibition phylogenetics whole exome sequencing

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
07 09 2021
Historique:
received: 30 12 2020
revised: 17 05 2021
accepted: 13 08 2021
entrez: 8 9 2021
pubmed: 9 9 2021
medline: 15 2 2022
Statut: ppublish

Résumé

High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and disease mortality. Recent clinical trials have shown that intensifying anti-androgen therapies administered before prostatectomy can induce pathologic complete responses or minimal residual disease, called exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we perform whole-exome and transcriptome sequencing on pre-treatment multi-regional tumor biopsies from exceptional responders (ERs) and non-responders (NRs, pathologic T3 or lymph node-positive disease) to intensive neoadjuvant anti-androgen therapies. Clonal SPOP mutation and SPOPL copy-number loss are exclusively observed in ERs, while clonal TP53 mutation and PTEN copy-number loss are exclusively observed in NRs. Transcriptional programs involving androgen signaling and TGF-β signaling are enriched in ERs and NRs, respectively. These findings may guide prospective validation studies of these molecular features in large HRLPC clinical cohorts treated with neoadjuvant anti-androgens to improve patient stratification.

Identifiants

DOI: 10.1016/j.celrep.2021.109665 PMID: 34496240
pubmed: 34496240
pii: S2211-1247(21)01109-8
doi: 10.1016/j.celrep.2021.109665
pii:
doi:

Substances chimiques

Adaptor Proteins, Vesicular Transport 0
Androgen Antagonists 0
Antineoplastic Agents, Hormonal 0
Nuclear Proteins 0
Repressor Proteins 0
SPOP protein, human 0
Prostate-Specific Antigen EC 3.4.21.77

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

109665

Subventions

Organisme : NCI NIH HHS
ID : T32 CA009172
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA239347
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008313
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA090381
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA163227
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA233100
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA222574
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227388
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests I.L. is a consultant for PACT Pharma. G.G. receives research funds from IBM and Pharmacylics and is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect, MSMutSig, and POLYSOLVER. E.M.V. is a consultant for Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Manifold Bio, Monte Rosa Therapeutics, and Janssen. E.M.V. provides research support to Novartis and Bristol-Myers Squibb. E.M.V. has equity in Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Monte Rosa Therapeutics, Manifold Bio, and Microsoft. E.M.V. receives travel reimbursement from Roche/Genentech. E.M.V. has institutional patents filed on ERCC2 mutations and chemotherapy response, chromatin mutations and immunotherapy response, and methods for clinical interpretation.

Auteurs

Alok K Tewari (AK)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Alexander T M Cheung (ATM)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Jett Crowdis (J)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Jake R Conway (JR)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Graduate Program in Bioinformatics and Integrative Genomics, Boston, MA 02115, USA.

Sabrina Y Camp (SY)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Stephanie A Wankowicz (SA)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Dimitri G Livitz (DG)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Jihye Park (J)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Rosina T Lis (RT)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Alice Bosma-Moody (A)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Meng Xiao He (MX)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Graduate Program in Biophysics, Boston, MA 02115, USA.

Saud H AlDubayan (SH)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.

Zhenwei Zhang (Z)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Rana R McKay (RR)

Division of Hematology/Oncology, University of California San Diego, San Diego, CA 92037, USA.

Ignaty Leshchiner (I)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Myles Brown (M)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Steven P Balk (SP)

Division of Cancer Biology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

Gad Getz (G)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.

Mary-Ellen Taplin (ME)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: mary_taplin@dfci.harvard.edu.

Eliezer M Van Allen (EM)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: eliezerm_vanallen@dfci.harvard.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines du transport vésiculaire › Protéines adaptatrices du transport vésiculaire › Molecular features of exceptional response to...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hormones, substituts d'hormones et antagonistes d'hormones › Antihormones › Antagonistes des androgènes › Molecular features of exceptional response to...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Antinéoplasiques hormonaux › Molecular features of exceptional response to...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Association de médicaments › Protocoles de polychimiothérapie antinéoplasique › Molecular features of exceptional response to...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Molecular features of exceptional response to...
questionsmedicales.fr › Thérapeutique › Association thérapeutique › Traitement néoadjuvant › Molecular features of exceptional response to...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Molecular features of exceptional response to...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Marqueurs biologiques tumoraux › Antigène spécifique de la prostate › Molecular features of exceptional response to...
questionsmedicales.fr › Procédures de chirurgie opératoire › Procédures de chirurgie urogénitale › Procédures de chirurgie urologique › Procédures de chirurgie urologique masculine › Prostatectomie › Molecular features of exceptional response to...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Molecular features of exceptional response to...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines de répression › Molecular features of exceptional response to...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Molecular features of exceptional response to...