Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma

Introduction: The percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPG...

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Autores: Mellid, Sara, Gil, Eduardo, Letón, Rocío, Caleiras, Eduardo, Honrado, Emiliano, Richter, Susan, Palacios, Nuria, Lahera, Marcos, Galofré , Juan C., López-Fernández, Adriá, Calatayud, Maria, Herrera-Martínez, Aura D., Galvez, María A., Matias-Guiu, Xavier, Balbín, Milagros, Korpershoek, Esther, Lim, Eugénie S., Maletta, Francesca, Lider , Sofia, Fliedner, Stephanie M. J., Bechmann, Nicole, Eisenhofer , Graeme, Canu, Letizia, Rapizzi, Elena, Bancos, Irina, Robledo, Mercedes, Cascón, Alberto
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2023
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/467663
Acesso em linha:https://doi.org/10.3389/fendo.2022.1070074
https://hdl.handle.net/10459.1/467663
Access Level:Acceso aberto
Palavra-chave:Pheochromocytoma
NF1
Germline mutation
DLST
MDH2
Co-occurrent mutations
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spelling Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paragangliomaMellid, SaraGil, EduardoLetón, RocíoCaleiras, EduardoHonrado, EmilianoRichter, SusanPalacios, NuriaLahera, MarcosGalofré , Juan C.López-Fernández, AdriáCalatayud, MariaHerrera-Martínez, Aura D.Galvez, María A.Matias-Guiu, XavierBalbín, MilagrosKorpershoek, EstherLim, Eugénie S.Maletta, FrancescaLider , SofiaFliedner, Stephanie M. J.Bechmann, NicoleEisenhofer , GraemeCanu, LetiziaRapizzi, ElenaBancos, IrinaRobledo, MercedesCascón, AlbertoPheochromocytomaNF1Germline mutationDLSTMDH2Co-occurrent mutationsIntroduction: The percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes. Methods: Herein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development. Results: Amongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an "intermediate signature" to suggest that both variants had a pathological role in tumour development. Discussion: In conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients.Frontiers Media2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.3389/fendo.2022.1070074https://hdl.handle.net/10459.1/467663reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3389/fendo.2022.1070074Frontiers in endocrinology, 2023, vol. 13, 1070074cc-by (c)Authors, 2023Attribution 4.0 Internationalinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:recercat.cat:10459.1/4676632026-05-29T05:05:01Z
dc.title.none.fl_str_mv Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma
title Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma
spellingShingle Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma
Mellid, Sara
Pheochromocytoma
NF1
Germline mutation
DLST
MDH2
Co-occurrent mutations
title_short Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma
title_full Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma
title_fullStr Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma
title_full_unstemmed Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma
title_sort Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma
dc.creator.none.fl_str_mv Mellid, Sara
Gil, Eduardo
Letón, Rocío
Caleiras, Eduardo
Honrado, Emiliano
Richter, Susan
Palacios, Nuria
Lahera, Marcos
Galofré , Juan C.
López-Fernández, Adriá
Calatayud, Maria
Herrera-Martínez, Aura D.
Galvez, María A.
Matias-Guiu, Xavier
Balbín, Milagros
Korpershoek, Esther
Lim, Eugénie S.
Maletta, Francesca
Lider , Sofia
Fliedner, Stephanie M. J.
Bechmann, Nicole
Eisenhofer , Graeme
Canu, Letizia
Rapizzi, Elena
Bancos, Irina
Robledo, Mercedes
Cascón, Alberto
author Mellid, Sara
author_facet Mellid, Sara
Gil, Eduardo
Letón, Rocío
Caleiras, Eduardo
Honrado, Emiliano
Richter, Susan
Palacios, Nuria
Lahera, Marcos
Galofré , Juan C.
López-Fernández, Adriá
Calatayud, Maria
Herrera-Martínez, Aura D.
Galvez, María A.
Matias-Guiu, Xavier
Balbín, Milagros
Korpershoek, Esther
Lim, Eugénie S.
Maletta, Francesca
Lider , Sofia
Fliedner, Stephanie M. J.
Bechmann, Nicole
Eisenhofer , Graeme
Canu, Letizia
Rapizzi, Elena
Bancos, Irina
Robledo, Mercedes
Cascón, Alberto
author_role author
author2 Gil, Eduardo
Letón, Rocío
Caleiras, Eduardo
Honrado, Emiliano
Richter, Susan
Palacios, Nuria
Lahera, Marcos
Galofré , Juan C.
López-Fernández, Adriá
Calatayud, Maria
Herrera-Martínez, Aura D.
Galvez, María A.
Matias-Guiu, Xavier
Balbín, Milagros
Korpershoek, Esther
Lim, Eugénie S.
Maletta, Francesca
Lider , Sofia
Fliedner, Stephanie M. J.
Bechmann, Nicole
Eisenhofer , Graeme
Canu, Letizia
Rapizzi, Elena
Bancos, Irina
Robledo, Mercedes
Cascón, Alberto
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Pheochromocytoma
NF1
Germline mutation
DLST
MDH2
Co-occurrent mutations
topic Pheochromocytoma
NF1
Germline mutation
DLST
MDH2
Co-occurrent mutations
description Introduction: The percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes. Methods: Herein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development. Results: Amongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an "intermediate signature" to suggest that both variants had a pathological role in tumour development. Discussion: In conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients.
publishDate 2023
dc.date.none.fl_str_mv 2023
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://doi.org/10.3389/fendo.2022.1070074
https://hdl.handle.net/10459.1/467663
url https://doi.org/10.3389/fendo.2022.1070074
https://hdl.handle.net/10459.1/467663
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/10.3389/fendo.2022.1070074
Frontiers in endocrinology, 2023, vol. 13, 1070074
dc.rights.none.fl_str_mv cc-by (c)Authors, 2023
Attribution 4.0 International
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by (c)Authors, 2023
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv 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
repository.name.fl_str_mv
repository.mail.fl_str_mv
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