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

Research output: Contribution to journalResearch articleContributedpeer-review


  • Sara Mellid - , Instituto de Salud Carlos III (Author)
  • Eduardo Gil - , Instituto de Salud Carlos III (Author)
  • Rocío Letón - , Instituto de Salud Carlos III (Author)
  • Eduardo Caleiras - , Instituto de Salud Carlos III (Author)
  • Emiliano Honrado - , Hospital Universitario de León (Author)
  • Susan Richter - , Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus Dresden (Author)
  • Nuria Palacios - , Universidad Autónoma de Madrid (Author)
  • Marcos Lahera - , Hospital Universitario de la Princesa (Author)
  • Juan C. Galofré - , University of Navarra (Author)
  • Adriá López-Fernández - , Vall d'Hebron Institute of Oncology (VHIO) (Author)
  • Maria Calatayud - , Complutense University (Author)
  • Aura D. Herrera-Martínez - , Hospital Universitario Reina Sofía (Author)
  • María A. Galvez - , Hospital Universitario Reina Sofía (Author)
  • Xavier Matias-Guiu - , University of Barcelona (Author)
  • Milagros Balbín - , University of Oviedo (Author)
  • Esther Korpershoek - , Erasmus University Rotterdam (Author)
  • Eugénie S. Lim - , Queen Mary University of London (Author)
  • Francesca Maletta - , Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino (Author)
  • Sofia Lider - , C.I. Parhon National Institute of Endocrinology (Author)
  • Stephanie M.J. Fliedner - , Universitätsklinikum Schleswig-Holstein - Campus Lübeck (Author)
  • Nicole Bechmann - , Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus Dresden (Author)
  • Graeme Eisenhofer - , Department of internal Medicine 3, University Hospital Carl Gustav Carus Dresden (Author)
  • Letizia Canu - , University of Florence (Author)
  • Elena Rapizzi - , University of Florence (Author)
  • Irina Bancos - , Mayo Clinic Rochester, MN (Author)
  • Mercedes Robledo - , Instituto de Salud Carlos III, CIBER - Center for Biomedical Research Network (Author)
  • Alberto Cascón - , Instituto de Salud Carlos III, CIBER - Center for Biomedical Research Network (Author)


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.


Original languageEnglish
Article number1070074
JournalFrontiers in endocrinology
Publication statusPublished - 25 Jan 2023

External IDs

PubMed 36760809
ORCID /0000-0002-6932-333X/work/142239664
ORCID /0000-0002-3549-2477/work/142244886


Sustainable Development Goals


  • co-occurrent mutations, DLST, germline mutation, MDH2, NF1, pheochromocytoma, Adrenal Gland Neoplasms/diagnosis, Pheochromocytoma/pathology, Genetic Predisposition to Disease, Humans, Paraganglioma/pathology, Mutation