Sex and smoking bias in the selection of somatic mutations in human bladder

Men are at higher risk of several cancer types than women1. For bladder cancer the risk is four times higher for reasons that are not clear2. Smoking is also a principal risk factor for several tumour types, including bladder cancer3. As tumourigenesis is driven by somatic mutations, we wondered whe...

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Autores: Calvet, Ferriol, Blanco Martínez Illescas, Raquel, Muiños Ballester, Ferran, Tretiakova, Maria, Latorre Esteves, Elena S., Fredrickson, Jeanne, Andrianova, Maria, Pellegrini, Stefano, Rosendahl Huber, Axel, Ramis Zaldívar, Joan Enric, An, Shuyi Charlotte, Thieme, Elana, Kohrn, Brendan F., Grau, Miguel L., González Pérez, Abel, López Bigas, Núria, Risques, Rosa Ana
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/223951
Acceso en línea:https://hdl.handle.net/2445/223951
Access Level:acceso abierto
Palabra clave:Càncer de bufeta
Factors sexuals en les malalties
Factors de risc en les malalties
Bladder cancer
Sex factors in disease
Risk factors in diseases
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spelling Sex and smoking bias in the selection of somatic mutations in human bladderCalvet, FerriolBlanco Martínez Illescas, RaquelMuiños Ballester, FerranTretiakova, MariaLatorre Esteves, Elena S.Fredrickson, JeanneAndrianova, MariaPellegrini, StefanoRosendahl Huber, AxelRamis Zaldívar, Joan EnricAn, Shuyi CharlotteThieme, ElanaKohrn, Brendan F.Grau, Miguel L.González Pérez, AbelLópez Bigas, NúriaRisques, Rosa AnaCàncer de bufetaFactors sexuals en les malaltiesFactors de risc en les malaltiesBladder cancerSex factors in diseaseRisk factors in diseasesMen are at higher risk of several cancer types than women1. For bladder cancer the risk is four times higher for reasons that are not clear2. Smoking is also a principal risk factor for several tumour types, including bladder cancer3. As tumourigenesis is driven by somatic mutations, we wondered whether the landscape of clones in the normal bladder differs by sex and smoking history. Using ultradeep duplex DNA sequencing (approximately 5,000x), we identified thousands of clonal driver mutations in 16 genes across 79 normal bladder samples from 45 people. Men had significantly more truncating driver mutations in RBM10, CDKN1A and ARID1A than women, despite similar levels of non-protein-affecting mutations. This result indicates stronger positive selection on driver truncating mutations in these genes in the male urothelium. We also found activating TERT promoter mutations driving clonal expansions in the normal bladder that were associated strongly with age and smoking. These findings indicate that bladder cancer risk factors, such as sex and smoking, shape the clonal landscape of the normal urothelium. The high number of mutations identified by this approach offers a new strategy to study the functional effect of thousands of mutations in vivo-natural saturation mutagenesis-that can be extended to other human tissues.Springer Nature2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/223951Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/s41586-025-09521-xNature, 2025https://doi.org/10.1038/s41586-025-09521-xcc-by (c) Calvet, Ferriol et al., 2025http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2239512026-05-27T06:46:51Z
dc.title.none.fl_str_mv Sex and smoking bias in the selection of somatic mutations in human bladder
title Sex and smoking bias in the selection of somatic mutations in human bladder
spellingShingle Sex and smoking bias in the selection of somatic mutations in human bladder
Calvet, Ferriol
Càncer de bufeta
Factors sexuals en les malalties
Factors de risc en les malalties
Bladder cancer
Sex factors in disease
Risk factors in diseases
title_short Sex and smoking bias in the selection of somatic mutations in human bladder
title_full Sex and smoking bias in the selection of somatic mutations in human bladder
title_fullStr Sex and smoking bias in the selection of somatic mutations in human bladder
title_full_unstemmed Sex and smoking bias in the selection of somatic mutations in human bladder
title_sort Sex and smoking bias in the selection of somatic mutations in human bladder
dc.creator.none.fl_str_mv Calvet, Ferriol
Blanco Martínez Illescas, Raquel
Muiños Ballester, Ferran
Tretiakova, Maria
Latorre Esteves, Elena S.
Fredrickson, Jeanne
Andrianova, Maria
Pellegrini, Stefano
Rosendahl Huber, Axel
Ramis Zaldívar, Joan Enric
An, Shuyi Charlotte
Thieme, Elana
Kohrn, Brendan F.
Grau, Miguel L.
González Pérez, Abel
López Bigas, Núria
Risques, Rosa Ana
author Calvet, Ferriol
author_facet Calvet, Ferriol
Blanco Martínez Illescas, Raquel
Muiños Ballester, Ferran
Tretiakova, Maria
Latorre Esteves, Elena S.
Fredrickson, Jeanne
Andrianova, Maria
Pellegrini, Stefano
Rosendahl Huber, Axel
Ramis Zaldívar, Joan Enric
An, Shuyi Charlotte
Thieme, Elana
Kohrn, Brendan F.
Grau, Miguel L.
González Pérez, Abel
López Bigas, Núria
Risques, Rosa Ana
author_role author
author2 Blanco Martínez Illescas, Raquel
Muiños Ballester, Ferran
Tretiakova, Maria
Latorre Esteves, Elena S.
Fredrickson, Jeanne
Andrianova, Maria
Pellegrini, Stefano
Rosendahl Huber, Axel
Ramis Zaldívar, Joan Enric
An, Shuyi Charlotte
Thieme, Elana
Kohrn, Brendan F.
Grau, Miguel L.
González Pérez, Abel
López Bigas, Núria
Risques, Rosa Ana
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer de bufeta
Factors sexuals en les malalties
Factors de risc en les malalties
Bladder cancer
Sex factors in disease
Risk factors in diseases
topic Càncer de bufeta
Factors sexuals en les malalties
Factors de risc en les malalties
Bladder cancer
Sex factors in disease
Risk factors in diseases
description Men are at higher risk of several cancer types than women1. For bladder cancer the risk is four times higher for reasons that are not clear2. Smoking is also a principal risk factor for several tumour types, including bladder cancer3. As tumourigenesis is driven by somatic mutations, we wondered whether the landscape of clones in the normal bladder differs by sex and smoking history. Using ultradeep duplex DNA sequencing (approximately 5,000x), we identified thousands of clonal driver mutations in 16 genes across 79 normal bladder samples from 45 people. Men had significantly more truncating driver mutations in RBM10, CDKN1A and ARID1A than women, despite similar levels of non-protein-affecting mutations. This result indicates stronger positive selection on driver truncating mutations in these genes in the male urothelium. We also found activating TERT promoter mutations driving clonal expansions in the normal bladder that were associated strongly with age and smoking. These findings indicate that bladder cancer risk factors, such as sex and smoking, shape the clonal landscape of the normal urothelium. The high number of mutations identified by this approach offers a new strategy to study the functional effect of thousands of mutations in vivo-natural saturation mutagenesis-that can be extended to other human tissues.
publishDate 2025
dc.date.none.fl_str_mv 2025
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/2445/223951
url https://hdl.handle.net/2445/223951
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41586-025-09521-x
Nature, 2025
https://doi.org/10.1038/s41586-025-09521-x
dc.rights.none.fl_str_mv cc-by (c) Calvet, Ferriol et al., 2025
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Calvet, Ferriol et al., 2025
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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