RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Elez Fernandez, Mª Elena; Ros Montañá, Fco. Javier; Fernández, Jose; Moreno-Cárdenas, Ana Belén; Arenillas Lallana, Carlota; Fasani, Roberta; Garcia Rodriguez, Ariadna; Gonzalo-Ruiz, Javier; Nuciforo, Paolo Giovanni; Vivancos Prellezo, Ana; Pérez López, Raquel; Tabernero, Josep; De Almeida Toledo, Rodrigo; Villacampa Javierre, Guillermo; Comas Navarro, Raquel; Dienstmann, Rodrigo; Bernatowicz, Kinga; Piris-Giménez, Alejandro

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Colorectal cancer; Predictive markers; Tumour biomarkers

Detalles Bibliográficos
Autores:	Elez Fernandez, Mª Elena, Ros Montañá, Fco. Javier, Fernández, Jose, Moreno-Cárdenas, Ana Belén, Arenillas Lallana, Carlota, Fasani, Roberta, Garcia Rodriguez, Ariadna, Gonzalo-Ruiz, Javier, Nuciforo, Paolo Giovanni, Vivancos Prellezo, Ana, Pérez López, Raquel, Tabernero, Josep, De Almeida Toledo, Rodrigo, Villacampa Javierre, Guillermo, Comas Navarro, Raquel, Dienstmann, Rodrigo, Bernatowicz, Kinga, Piris-Giménez, Alejandro
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2022
País:	España
Institución:	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:	Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:	oai:recercat.cat:11351/8672
Acceso en línea:	https://hdl.handle.net/11351/8672
Access Level:	acceso abierto
Palabra clave:	Anomalies cromosòmiques Còlon - Càncer - Tractament Recte - Càncer - Tractament DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms Other subheadings::Other subheadings::Other subheadings::/drug therapy PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación

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network_acronym_str	ES
network_name_str	España
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dc.title.none.fl_str_mv	RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer
title	RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer
spellingShingle	RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer Elez Fernandez, Mª Elena Anomalies cromosòmiques Còlon - Càncer - Tractament Recte - Càncer - Tractament DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms Other subheadings::Other subheadings::Other subheadings::/drug therapy PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación
title_short	RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer
title_full	RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer
title_fullStr	RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer
title_full_unstemmed	RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer
title_sort	RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer
dc.creator.none.fl_str_mv	Elez Fernandez, Mª Elena Ros Montañá, Fco. Javier Fernández, Jose Moreno-Cárdenas, Ana Belén Arenillas Lallana, Carlota Fasani, Roberta Garcia Rodriguez, Ariadna Gonzalo-Ruiz, Javier Nuciforo, Paolo Giovanni Vivancos Prellezo, Ana Pérez López, Raquel Tabernero, Josep De Almeida Toledo, Rodrigo Villacampa Javierre, Guillermo Comas Navarro, Raquel Dienstmann, Rodrigo Bernatowicz, Kinga Piris-Giménez, Alejandro
author	Elez Fernandez, Mª Elena
author_facet	Elez Fernandez, Mª Elena Ros Montañá, Fco. Javier Fernández, Jose Moreno-Cárdenas, Ana Belén Arenillas Lallana, Carlota Fasani, Roberta Garcia Rodriguez, Ariadna Gonzalo-Ruiz, Javier Nuciforo, Paolo Giovanni Vivancos Prellezo, Ana Pérez López, Raquel Tabernero, Josep De Almeida Toledo, Rodrigo Villacampa Javierre, Guillermo Comas Navarro, Raquel Dienstmann, Rodrigo Bernatowicz, Kinga Piris-Giménez, Alejandro
author_role	author
author2	Ros Montañá, Fco. Javier Fernández, Jose Moreno-Cárdenas, Ana Belén Arenillas Lallana, Carlota Fasani, Roberta Garcia Rodriguez, Ariadna Gonzalo-Ruiz, Javier Nuciforo, Paolo Giovanni Vivancos Prellezo, Ana Pérez López, Raquel Tabernero, Josep De Almeida Toledo, Rodrigo Villacampa Javierre, Guillermo Comas Navarro, Raquel Dienstmann, Rodrigo Bernatowicz, Kinga Piris-Giménez, Alejandro
author2_role	author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Institut Català de la Salut [Elez E] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ros J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy. [Fernández J, Villacampa G, Moreno-Cárdenas AB, Bernatowicz K, Comas R, Fasani R, Garcia A, Gonzalo-Ruiz J, Piris-Gimenez A, Nuciforo P, Vivancos A, Dienstmann R] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Arenillas C, Toledo RA] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Institute of Health Carlos III (ISCIII), Madrid, Spain. [Perez-Lopez R] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei de Radiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Tabernero J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Institute of Health Carlos III (ISCIII), Madrid, Spain. UVic-UCC, IOB-Quirón, Barcelona, Spain Vall d'Hebron Barcelona Hospital Campus
dc.subject.none.fl_str_mv	Anomalies cromosòmiques Còlon - Càncer - Tractament Recte - Càncer - Tractament DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms Other subheadings::Other subheadings::Other subheadings::/drug therapy PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación
topic	Anomalies cromosòmiques Còlon - Càncer - Tractament Recte - Càncer - Tractament DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms Other subheadings::Other subheadings::Other subheadings::/drug therapy PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación
description	Colorectal cancer; Predictive markers; Tumour biomarkers
publishDate	2022
dc.date.none.fl_str_mv	2022 2022 2022
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/11351/8672
url	https://hdl.handle.net/11351/8672
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Nature Medicine;28 https://doi.org/10.1038/s41591-022-01976-z info:eu-repo/grantAgreement/ES/PE2013-2016/CB16%2F12%2F00259 info:eu-repo/grantAgreement/ES/PERIS2016-2020/SLT008%2F18%2F00198 info:eu-repo/grantAgreement/ES/PERIS2016-2020/SLT008%2F18%2F00205 info:eu-repo/grantAgreement/ES/PE2017-2020/CEX2020-001024-S info:eu-repo/grantAgreement/ES/PE2013-2016/PI18%2F01395 info:eu-repo/grantAgreement/ES/PE2017-2020/PI21%2F01019 info:eu-repo/grantAgreement/ES/PE2013-2016/CP17%2F00199 info:eu-repo/grantAgreement/ES/PE2013-2016/PI17%2F00947 info:eu-repo/grantAgreement/ES/PE2017-2020/PI20%2F00968 info:eu-repo/grantAgreement/ES/PE2017-2020/ECT2020-000827
dc.rights.none.fl_str_mv	Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess
rights_invalid_str_mv	Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Nature Portfolio
publisher.none.fl_str_mv	Nature Portfolio
dc.source.none.fl_str_mv	Scientia reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str	Recercat. Dipósit de la Recerca de Catalunya
collection	Recercat. Dipósit de la Recerca de Catalunya
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spelling	RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancerElez Fernandez, Mª ElenaRos Montañá, Fco. JavierFernández, JoseMoreno-Cárdenas, Ana BelénArenillas Lallana, CarlotaFasani, RobertaGarcia Rodriguez, AriadnaGonzalo-Ruiz, JavierNuciforo, Paolo GiovanniVivancos Prellezo, AnaPérez López, RaquelTabernero, JosepDe Almeida Toledo, RodrigoVillacampa Javierre, GuillermoComas Navarro, RaquelDienstmann, RodrigoBernatowicz, KingaPiris-Giménez, AlejandroAnomalies cromosòmiquesCòlon - Càncer - TractamentRecte - Càncer - TractamentDISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal NeoplasmsOther subheadings::Other subheadings::Other subheadings::/drug therapyPHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::MutationENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectalesOtros calificadores::Otros calificadores::Otros calificadores::/farmacoterapiaFENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutaciónColorectal cancer; Predictive markers; Tumour biomarkersCáncer colorrectal; Marcadores predictivos; Biomarcadores tumoralesCàncer colorrectal; Marcadors predictius; Biomarcadors tumoralsAnti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment, the FERO Foundation for their funding support, the Consorcio Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, CB16/12/00259) from the Institute of Health Carlos III (ISCIII), Ministry of Science and Innovation, and the Department of Health (Generalitat de Catalunya, SLT008/18/00198 and SLT008/18/00205) for their support on this research. Authors acknowledge financial support from the State Agency for Research (Agencia Estatal de Investigación) (CEX2020-001024-S / AEI / 10.13039 /501100011033). This research is funded by the SCITRON program; Novartis funded the genomics characterization by WES of samples from 28 patients from the discovery cohort and had no influence on data analysis/interpretation or writing of the paper (3003145512 to R.A.T.). S.Li. is financially supported by a Chinese Scholarship Council PhD fellowship (201909370083 to S. Li). R.P.-L. is supported by a CRIS Foundation Talent Award (TALENT19-05), the FERO Foundation, the Instituto de Salud Carlos III-Investigación en Salud (PI18/01395 and PI21/01019 to R.P.-L.) and the Prostate Cancer Foundation (Young Investigator Award). This work was supported by the Miguel Servet-I Research Award from ISCIII of the Ministry of Economy (CP17/00199 to R.A.T.), the Olga Torres Foundation Award to emerging researchers (2601 to R.A.T.), the ISCIII-FEDER (PI17/00947 and PI20/00968 to E.E.), and the Fundación AECC (CLSEN19001ELEZ to E.E.) and Ministry of Science and Innovation (Europa Redes y Gestores, ECT2020-000827 to E.E.).Nature PortfolioInstitut Català de la Salut[Elez E] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ros J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy. [Fernández J, Villacampa G, Moreno-Cárdenas AB, Bernatowicz K, Comas R, Fasani R, Garcia A, Gonzalo-Ruiz J, Piris-Gimenez A, Nuciforo P, Vivancos A, Dienstmann R] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Arenillas C, Toledo RA] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Institute of Health Carlos III (ISCIII), Madrid, Spain. [Perez-Lopez R] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei de Radiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Tabernero J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Institute of Health Carlos III (ISCIII), Madrid, Spain. UVic-UCC, IOB-Quirón, Barcelona, SpainVall d'Hebron Barcelona Hospital Campus202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/11351/8672Scientiareponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésNature Medicine;28https://doi.org/10.1038/s41591-022-01976-zinfo:eu-repo/grantAgreement/ES/PE2013-2016/CB16%2F12%2F00259info:eu-repo/grantAgreement/ES/PERIS2016-2020/SLT008%2F18%2F00198info:eu-repo/grantAgreement/ES/PERIS2016-2020/SLT008%2F18%2F00205info:eu-repo/grantAgreement/ES/PE2017-2020/CEX2020-001024-Sinfo:eu-repo/grantAgreement/ES/PE2013-2016/PI18%2F01395info:eu-repo/grantAgreement/ES/PE2017-2020/PI21%2F01019info:eu-repo/grantAgreement/ES/PE2013-2016/CP17%2F00199info:eu-repo/grantAgreement/ES/PE2013-2016/PI17%2F00947info:eu-repo/grantAgreement/ES/PE2017-2020/PI20%2F00968info:eu-repo/grantAgreement/ES/PE2017-2020/ECT2020-000827Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:11351/86722026-05-29T05:05:01Z
score	15.811543

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

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