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Title: | Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma |
Author: | Mellid, Sara Gil, Eduardo Letón, Rocío Caleiras, Eduardo Honrado, Emiliano Richter, Susan Palacios, Nuria Lahera, Marcos Galofré, Juan C. López Fernández, Adrià 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 |
Keywords: | Feocromocitoma Mutació (Biologia) Malalties hereditàries Pheochromocytoma Mutation (Biology) Genetic diseases |
Issue Date: | 25-Jan-2023 |
Publisher: | Frontiers Media SA |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.3389/fendo.2022.1070074 |
It is part of: | Frontiers in Endocrinology, 2023, vol. 13, num. 1070074 |
URI: | http://hdl.handle.net/2445/198361 |
Related resource: | https://doi.org/10.3389/fendo.2022.1070074 |
ISSN: | 1664-2392 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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