TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features

Pérez-Carretero, Claudia; Hernández-Sánchez, María; González, Teresa; Quijada Álamo, Miguel; Martín Izquierdo, Marta; Santos-Mínguez, Sandra; Miguel-García, Cristina; Vidal, María-Jesús; García-De-Coca, Alfonso; Galende, Josefina; Pardal, Emilia; Aguilar, Carlos; Vargas-Pabón, Manuel; Dávila, Julio; Gascón-Y-Marín, Isabel; Hernández-Rivas, José-Ángel; Benito Sánchez, Rocío; Hernández-Rivas, Jesús-María; Rodríguez Vicente, Ana E.

TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features

[EN]Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a to...

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Authors:	Pérez-Carretero, Claudia, Hernández-Sánchez, María, González, Teresa, Quijada Álamo, Miguel, Martín Izquierdo, Marta, Santos-Mínguez, Sandra, Miguel-García, Cristina, Vidal, María-Jesús, García-De-Coca, Alfonso, Galende, Josefina, Pardal, Emilia, Aguilar, Carlos, Vargas-Pabón, Manuel, Dávila, Julio, Gascón-Y-Marín, Isabel, Hernández-Rivas, José-Ángel, Benito Sánchez, Rocío, Hernández-Rivas, Jesús-María, Rodríguez Vicente, Ana E.
Format:	article
Status:	Published version
Publication Date:	2022
Country:	España
Institution:	Universidad de Salamanca (USAL)
Repository:	GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:	oai:dnet:gredos______::97caea53fc22db75389299a630a620f4
Online Access:	http://hdl.handle.net/10366/171344
Access Level:	Open access
Keyword:	B-Cell Chronic Lymphocytic Leukemia Genes Immunoglobulin Heavy Chain Humans Mutation Prognosis TNF Receptor-Associated Factor 3 Biología Molecular Molecular Biology 24 Ciencias de la Vida genes pronóstico biología molecular humanos mutación leucemia factor 3 asociado a receptores TNF

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spelling	TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical featuresPérez-Carretero, ClaudiaHernández-Sánchez, MaríaGonzález, TeresaQuijada Álamo, MiguelMartín Izquierdo, MartaSantos-Mínguez, SandraMiguel-García, CristinaVidal, María-JesúsGarcía-De-Coca, AlfonsoGalende, JosefinaPardal, EmiliaAguilar, CarlosVargas-Pabón, ManuelDávila, JulioGascón-Y-Marín, IsabelHernández-Rivas, José-ÁngelBenito Sánchez, RocíoHernández-Rivas, Jesús-MaríaRodríguez Vicente, Ana E.B-CellChronicLymphocyticLeukemiaGenesImmunoglobulin Heavy ChainHumansMutationPrognosisTNF Receptor-Associated Factor 3Biología MolecularPrognosisMutationLeukemiaHumansMolecular BiologyGenesTNF Receptor-Associated Factor 324 Ciencias de la Vidagenespronósticobiología molecularhumanosmutaciónleucemiafactor 3 asociado a receptores TNF[EN]Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break-apart probe, and 54 (6.2%) had a 300 kb deletion of 3'IGH (del-3'IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next-generation sequencing of 317 untreated CLLs (54 del-3'IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del-3'IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del-3'IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del-3'IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del-3'IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients.202620262022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10366/171344reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)Inglés22GMO;1Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:dnet:gredos______::97caea53fc22db75389299a630a620f42026-06-07T06:28:51Z
dc.title.none.fl_str_mv	TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features
title	TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features
spellingShingle	TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features Pérez-Carretero, Claudia B-Cell Chronic Lymphocytic Leukemia Genes Immunoglobulin Heavy Chain Humans Mutation Prognosis TNF Receptor-Associated Factor 3 Biología Molecular Prognosis Mutation Leukemia Humans Molecular Biology Genes TNF Receptor-Associated Factor 3 24 Ciencias de la Vida genes pronóstico biología molecular humanos mutación leucemia factor 3 asociado a receptores TNF
title_short	TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features
title_full	TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features
title_fullStr	TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features
title_full_unstemmed	TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features
title_sort	TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features
dc.creator.none.fl_str_mv	Pérez-Carretero, Claudia Hernández-Sánchez, María González, Teresa Quijada Álamo, Miguel Martín Izquierdo, Marta Santos-Mínguez, Sandra Miguel-García, Cristina Vidal, María-Jesús García-De-Coca, Alfonso Galende, Josefina Pardal, Emilia Aguilar, Carlos Vargas-Pabón, Manuel Dávila, Julio Gascón-Y-Marín, Isabel Hernández-Rivas, José-Ángel Benito Sánchez, Rocío Hernández-Rivas, Jesús-María Rodríguez Vicente, Ana E.
author	Pérez-Carretero, Claudia
author_facet	Pérez-Carretero, Claudia Hernández-Sánchez, María González, Teresa Quijada Álamo, Miguel Martín Izquierdo, Marta Santos-Mínguez, Sandra Miguel-García, Cristina Vidal, María-Jesús García-De-Coca, Alfonso Galende, Josefina Pardal, Emilia Aguilar, Carlos Vargas-Pabón, Manuel Dávila, Julio Gascón-Y-Marín, Isabel Hernández-Rivas, José-Ángel Benito Sánchez, Rocío Hernández-Rivas, Jesús-María Rodríguez Vicente, Ana E.
author_role	author
author2	Hernández-Sánchez, María González, Teresa Quijada Álamo, Miguel Martín Izquierdo, Marta Santos-Mínguez, Sandra Miguel-García, Cristina Vidal, María-Jesús García-De-Coca, Alfonso Galende, Josefina Pardal, Emilia Aguilar, Carlos Vargas-Pabón, Manuel Dávila, Julio Gascón-Y-Marín, Isabel Hernández-Rivas, José-Ángel Benito Sánchez, Rocío Hernández-Rivas, Jesús-María Rodríguez Vicente, Ana E.
author2_role	author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	B-Cell Chronic Lymphocytic Leukemia Genes Immunoglobulin Heavy Chain Humans Mutation Prognosis TNF Receptor-Associated Factor 3 Biología Molecular Prognosis Mutation Leukemia Humans Molecular Biology Genes TNF Receptor-Associated Factor 3 24 Ciencias de la Vida genes pronóstico biología molecular humanos mutación leucemia factor 3 asociado a receptores TNF
topic	B-Cell Chronic Lymphocytic Leukemia Genes Immunoglobulin Heavy Chain Humans Mutation Prognosis TNF Receptor-Associated Factor 3 Biología Molecular Prognosis Mutation Leukemia Humans Molecular Biology Genes TNF Receptor-Associated Factor 3 24 Ciencias de la Vida genes pronóstico biología molecular humanos mutación leucemia factor 3 asociado a receptores TNF
description	[EN]Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break-apart probe, and 54 (6.2%) had a 300 kb deletion of 3'IGH (del-3'IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next-generation sequencing of 317 untreated CLLs (54 del-3'IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del-3'IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del-3'IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del-3'IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del-3'IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients.
publishDate	2022
dc.date.none.fl_str_mv	2022 2026 2026
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	http://hdl.handle.net/10366/171344
url	http://hdl.handle.net/10366/171344
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	22GMO;1
dc.rights.none.fl_str_mv	Attribution 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess
rights_invalid_str_mv	Attribution 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.source.none.fl_str_mv	reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca instname:Universidad de Salamanca (USAL)
instname_str	Universidad de Salamanca (USAL)
reponame_str	GREDOS. Repositorio Institucional de la Universidad de Salamanca
collection	GREDOS. Repositorio Institucional de la Universidad de Salamanca
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,81155

TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features

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