Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma

Background: tobacco is the main risk factor for developing lung cancer. Yet, some heavy smokers do not develop lung cancer at advanced ages while others develop it at young ages. Here, we assess for the first time the genetic background of these clinically relevant extreme phenotypes using whole exo...

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Autores: Patiño García, Ana, Guruceaga, Elizabeth, Segura, Víctor, Sánchez Bayona, Rodrigo, Andueza, María Pilar, Tamayo Uria, Ibon, Serrano, Guillermo, Fusco, Juan Pablo, Pajares Villandiego, María Josefa, Gúrpide, Alfonso, Ocón, Marimar, Sanmamed, Miguel F., Rodríguez Ruiz, María, Melero, Ignacio, Lozano, María Dolores, Andrea, Carlos de, Pita, Guillermo, González Neira, Anna, González, Alvaro, Zulueta, Javier J., Montuenga, Luis M., Pío, Rubén, Pérez Gracia, José Luis
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad Pública de Navarra
Repositorio:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
OAI Identifier:oai:academica-e.unavarra.es:2454/41809
Acceso en línea:https://hdl.handle.net/2454/41809
Access Level:acceso abierto
Palabra clave:Cancer risk
Extreme phenotypes
Whole exome sequencing (WES)
Tobacco
Lung adenocarcinoma
ALPK2
HLA-A
PARP4
NOQ1
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spelling Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinomaPatiño García, AnaGuruceaga, ElizabethSegura, VíctorSánchez Bayona, RodrigoAndueza, María PilarTamayo Uria, IbonSerrano, GuillermoFusco, Juan PabloPajares Villandiego, María JosefaGúrpide, AlfonsoOcón, MarimarSanmamed, Miguel F.Rodríguez Ruiz, MaríaMelero, IgnacioLozano, María DoloresAndrea, Carlos dePita, GuillermoGonzález Neira, AnnaGonzález, AlvaroZulueta, Javier J.Montuenga, Luis M.Pío, RubénPérez Gracia, José LuisCancer riskExtreme phenotypesWhole exome sequencing (WES)TobaccoLung adenocarcinomaALPK2HLA-APARP4NOQ1Background: tobacco is the main risk factor for developing lung cancer. Yet, some heavy smokers do not develop lung cancer at advanced ages while others develop it at young ages. Here, we assess for the first time the genetic background of these clinically relevant extreme phenotypes using whole exome sequencing (WES). Methods: we performed WES of germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age ( extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (extreme controls, n=50). We selected non-synonymous variants located in exonic regions and consensus splice sites of the genes that showed significantly different allelic frequencies between both cohorts. We validated our results in all the additional extreme cases (i.e., heavy smokers who developed lung adenocarcinoma at an early age) available from The Cancer Genome Atlas (TCGA). Results: the mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.6 and 56.8 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 108 of these in extreme cases selected from TCGA. Nine validated variants, located in relevant cancer related genes, such as PARP4, HLA-A or NQO1, among others, achieved statistical significance in the False Discovery Rate test. The most significant validated variant (P=4.48x10(-5)) was located in the tumor-suppressor gene ALPK2. Conclusions: we describe genetic variants associated with extreme phenotypes of high and low risk for the development of tobacco-induced lung adenocarcinoma. Our results and our strategy may help to identify high-risk subjects and to develop new therapeutic strategies.This work was supported by the Spanish Society of Medical Oncology; Fundación SEOM and Fundación Salud 2000; and Government of Navarra. LMM research work is supported by Foundation for Applied Medical Research (FIMA), Fundación Científica de la Asociación Espanola Contra el Cáncer, Fundación Ramón Areces, and Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional 'Una manera de hacer Europa' (PI19/00098).AME PublishingCiencias de la SaludOsasun ZientziakGobierno de Navarra / Nafarroako Gobernua2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2454/41809reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarrainstname:Universidad Pública de NavarraInglés© Translational Lung Cancer Research. Creative Commons Attribution-NonCommercial-NoDerivs 4.0 Internationalhttps://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:academica-e.unavarra.es:2454/418092026-06-17T12:41:47Z
dc.title.none.fl_str_mv Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma
title Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma
spellingShingle Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma
Patiño García, Ana
Cancer risk
Extreme phenotypes
Whole exome sequencing (WES)
Tobacco
Lung adenocarcinoma
ALPK2
HLA-A
PARP4
NOQ1
title_short Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma
title_full Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma
title_fullStr Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma
title_full_unstemmed Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma
title_sort Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma
dc.creator.none.fl_str_mv Patiño García, Ana
Guruceaga, Elizabeth
Segura, Víctor
Sánchez Bayona, Rodrigo
Andueza, María Pilar
Tamayo Uria, Ibon
Serrano, Guillermo
Fusco, Juan Pablo
Pajares Villandiego, María Josefa
Gúrpide, Alfonso
Ocón, Marimar
Sanmamed, Miguel F.
Rodríguez Ruiz, María
Melero, Ignacio
Lozano, María Dolores
Andrea, Carlos de
Pita, Guillermo
González Neira, Anna
González, Alvaro
Zulueta, Javier J.
Montuenga, Luis M.
Pío, Rubén
Pérez Gracia, José Luis
author Patiño García, Ana
author_facet Patiño García, Ana
Guruceaga, Elizabeth
Segura, Víctor
Sánchez Bayona, Rodrigo
Andueza, María Pilar
Tamayo Uria, Ibon
Serrano, Guillermo
Fusco, Juan Pablo
Pajares Villandiego, María Josefa
Gúrpide, Alfonso
Ocón, Marimar
Sanmamed, Miguel F.
Rodríguez Ruiz, María
Melero, Ignacio
Lozano, María Dolores
Andrea, Carlos de
Pita, Guillermo
González Neira, Anna
González, Alvaro
Zulueta, Javier J.
Montuenga, Luis M.
Pío, Rubén
Pérez Gracia, José Luis
author_role author
author2 Guruceaga, Elizabeth
Segura, Víctor
Sánchez Bayona, Rodrigo
Andueza, María Pilar
Tamayo Uria, Ibon
Serrano, Guillermo
Fusco, Juan Pablo
Pajares Villandiego, María Josefa
Gúrpide, Alfonso
Ocón, Marimar
Sanmamed, Miguel F.
Rodríguez Ruiz, María
Melero, Ignacio
Lozano, María Dolores
Andrea, Carlos de
Pita, Guillermo
González Neira, Anna
González, Alvaro
Zulueta, Javier J.
Montuenga, Luis M.
Pío, Rubén
Pérez Gracia, José Luis
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ciencias de la Salud
Osasun Zientziak
Gobierno de Navarra / Nafarroako Gobernua
dc.subject.none.fl_str_mv Cancer risk
Extreme phenotypes
Whole exome sequencing (WES)
Tobacco
Lung adenocarcinoma
ALPK2
HLA-A
PARP4
NOQ1
topic Cancer risk
Extreme phenotypes
Whole exome sequencing (WES)
Tobacco
Lung adenocarcinoma
ALPK2
HLA-A
PARP4
NOQ1
description Background: tobacco is the main risk factor for developing lung cancer. Yet, some heavy smokers do not develop lung cancer at advanced ages while others develop it at young ages. Here, we assess for the first time the genetic background of these clinically relevant extreme phenotypes using whole exome sequencing (WES). Methods: we performed WES of germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age ( extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (extreme controls, n=50). We selected non-synonymous variants located in exonic regions and consensus splice sites of the genes that showed significantly different allelic frequencies between both cohorts. We validated our results in all the additional extreme cases (i.e., heavy smokers who developed lung adenocarcinoma at an early age) available from The Cancer Genome Atlas (TCGA). Results: the mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.6 and 56.8 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 108 of these in extreme cases selected from TCGA. Nine validated variants, located in relevant cancer related genes, such as PARP4, HLA-A or NQO1, among others, achieved statistical significance in the False Discovery Rate test. The most significant validated variant (P=4.48x10(-5)) was located in the tumor-suppressor gene ALPK2. Conclusions: we describe genetic variants associated with extreme phenotypes of high and low risk for the development of tobacco-induced lung adenocarcinoma. Our results and our strategy may help to identify high-risk subjects and to develop new therapeutic strategies.
publishDate 2021
dc.date.none.fl_str_mv 2021
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/2454/41809
url https://hdl.handle.net/2454/41809
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv AME Publishing
publisher.none.fl_str_mv AME Publishing
dc.source.none.fl_str_mv reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
instname:Universidad Pública de Navarra
instname_str Universidad Pública de Navarra
reponame_str Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
collection Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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