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 PPGL...

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Detalhes bibliográficos
Autores: Mellid, Sara, Gil, Eduardo, Letón, Rocío, Caleiras, Eduardo, Honrado, Emiliano, Richter, Susan, Palacios, Nuria, Lahera, Marcos, Galofré, Juan C., López Fernández, Adrià, Calatayud, María, Herrera Martínez, Aura D., Galvez, María A., Matias-Guiu, Xavier, 1958-, 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:2445/198361
Acesso em linha:https://hdl.handle.net/2445/198361
Access Level:Acceso aberto
Palavra-chave:Feocromocitoma
Mutació (Biologia)
Malalties hereditàries
Pheochromocytoma
Mutation (Biology)
Genetic diseases
Descrição
Resumo: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. MethodsHerein 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. ResultsAmongst 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. DiscussionIn 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.

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