Scientific publications

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

Jan 25, 2023 | Magazine: Frontiers in Endocrinology

Sara Mellid  1 , Eduardo Gil  1 , Rocío Letón  1 , Eduardo Caleiras  2 , Emiliano Honrado  3 , Susan Richter  4 , Nuria Palacios  5 , Marcos Lahera  6 , Juan C Galofré  7 , Adriá López-Fernández  8 , Maria Calatayud  9 , Aura D Herrera-Martínez  10 , María A Galvez  10 , Xavier Matias-Guiu  11 , Milagros Balbín  12 , Esther Korpershoek  13 , Eugénie S Lim  14 , Francesca Maletta  15 , Sofia Lider  16 , Stephanie M J Fliedner  17 , Nicole Bechmann  4 , Graeme Eisenhofer  4   18 , Letizia Canu  19 , Elena Rapizzi  19 , Irina Bancos  20 , Mercedes Robledo  1   21 , Alberto Cascón  1   21

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.

CITATION  Front Endocrinol (Lausanne). 2023 Jan 25;13:1070074.  doi: 10.3389/fendo.2022.1070074.