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Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma
  1. Laurène Ben Aim1,
  2. Pascal Pigny2,
  3. Luis Jaime Castro-Vega3,4,
  4. Alexandre Buffet3,4,
  5. Laurence Amar3,4,5,
  6. Jérôme Bertherat3,6,7,
  7. Delphine Drui8,
  8. Isabelle Guilhem9,
  9. Eric Baudin10,11,
  10. Charlotte Lussey-Lepoutre4,12,
  11. Carole Corsini13,
  12. Gérard Chabrier14,
  13. Claire Briet15,
  14. Laurence Faivre16,
  15. Catherine Cardot-Bauters17,
  16. Judith Favier3,4,
  17. Anne-Paule Gimenez-Roqueplo1,3,4,
  18. Nelly Burnichon1,3,4
  1. 1 Genetics department, Assistance Publique-Hôpitaux de Paris, Hôpitaleuropéen Georges Pompidou, F-75015, Paris, France
  2. 2 Institut de Biochimie & Biologie Moléculaire, CHU Lille, F-59037 Lille, France
  3. 3 Faculté de Médecine, Paris Descartes University, PRES Sorbonne ParisCité, F-75006 Paris, France
  4. 4 UMR970, Paris-Cardiovascular research Center, INSERM, F-75015, Paris, France
  5. 5 Hypertension Unit, Assistance Publique-Hôpitaux de Paris, Hôpitaleuropéen Georges Pompidou, F-75015, Paris, France
  6. 6 Centerfor Rare Adrenal Diseases, Endocrinology Department, CochinHospital, Assistance Publique Hôpitaux de Paris, F-75014, Paris, France
  7. 7 CNRS (UMR8104)/Inserm (U1016), Cochin Institute, Paris Descartes University, F-75014, Paris, France
  8. 8 L’institut du thorax, Department of Endocrinology, Centre Hospitalier Universitaire Nantes, F-44000 Nantes, France
  9. 9 Service d’Endocrinologie-Diabétologie-Nutrition, Centre Hospitalier Universitaire de Rennes, Hôpital Sud, Rennes, France
  10. 10 Service de Médecine Nucléaire et de Cancérologie Endocrinienne, Gustave Roussy, Villejuif, Île-de-France, France
  11. 11 INSERMUMR 1185, Université Paris Sud, F-94276, Le Kremlin-Bicêtre, France
  12. 12 Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University Cancer Institute, F-75013, Paris, France
  13. 13 Medical Genetics Department, Centre Hospitalier Regional Universitaire de Montpellier, Montpellier, Languedoc-Roussillon, France
  14. 14 Service de Médecine Interne, Endocrinologie, Nutrition, CHU de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  15. 15 Endocrinology Department, Centre Hospitalier Universitaire d’Angers, Angers, France
  16. 16 Medical Oncogenetics, Centre Hospitalier Universitaire de Dijon, Dijon, France
  17. 17 Service d’Endocrinologie, CHU Lille, Lille, France
  1. Correspondence to Dr Nelly Burnichon, UMR970, Paris-Cardiovascular research Center INSERM F-75015, Paris France; nelly.burnichon{at}


Background Knowing the genetic status of patients affected by paragangliomas and pheochromocytomas (PPGL) is important for the guidance of their management and their relatives. Our objective was to improve the diagnostic performances of PPGL genetic testing by next-generation sequencing (NGS).

Methods We developed a custom multigene panel, which includes 17 PPGL genes and is compatible with both germline and tumour DNA screening. The NGS assay was first validated in a retrospective cohort of 201 frozen tumour DNAs and then applied prospectively to 623 DNAs extracted from leucocytes, frozen or paraffin-embedded PPGL tumours.

Results In the retrospective cohort, the sensitivity of the NGS assay was evaluated at 100% for point and indels mutations and 86% for large rearrangements. The mutation rate was re-evaluated from 65% (132/202) to 78% (156/201) after NGS analysis. In the prospective cohort, NGS detected not only germline and somatic mutations but also co-occurring variants and mosaicism. A mutation was identified in 74% of patients for whom both germline and tumour DNA were available.

Conclusion The analysis of 824 DNAs from patients with PPGL demonstrated that NGS assay significantly improves the performances of PPGL genetic testing compared with conventional methods, increasing the rate of identified mutations and identifying rare genetic mechanisms.

  • next generation sequencing
  • paraganglioma
  • pheochromocytoma
  • somatic mutations
  • mosaicism

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  • Contributors LBA, PP, LJCV and AB: performed the experiments. LBA, PP, JF, APGR and NB: designed the experiments. LBA, PP, LJCV, AB, JF, APGR and NB: collected the data and contributed to the interpretation of results. LA, JB, DD, IG, EB, CLL, CC, GC, CB, LF, CCB and APGR: provide and cared for studied patients. LBA, JF, APGR and NB: wrote the manuscript. APGR and NB: supervised the study. All authors approved the final version of the manuscript.

  • Funding This work has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 633983 and by the Institut National du Cancer and the Direction Générale de l’Offre de Soins (PRT-K 2014, COMETE-TACTIC, INCa-DGOS_8663). N. Burnichon received financial support from the Cancer Research for Personalized Medicine - CARPEM project (Site de Recherche Intégré sur le Cancer – SIRIC). The team is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée). This work is part of the ‘Cartes d’Identité des Tumeurs (CIT) program’ funded and developed by the ‘Ligue Nationale contre le Cancer’ (

  • Competing interests None declared.

  • Ethics approval Institutional Review Board (IRB 00003835, Comité de Protection des Personnes Ile de France IV).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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