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Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients
  1. Maria Currás-Freixes1,
  2. Lucía Inglada-Pérez1,2,
  3. Veronika Mancikova1,
  4. Cristina Montero-Conde1,
  5. Rocío Letón1,
  6. Iñaki Comino-Méndez1,
  7. María Apellániz-Ruiz1,
  8. Lara Sánchez-Barroso1,
  9. Miguel Aguirre Sánchez-Covisa3,
  10. Victoria Alcázar4,
  11. Javier Aller5,
  12. Cristina Álvarez-Escolá6,
  13. Víctor M Andía-Melero7,
  14. Sharona Azriel-Mira8,
  15. María Calatayud-Gutiérrez9,
  16. José Ángel Díaz10,
  17. Alberto Díez-Hernández11,
  18. Cristina Lamas-Oliveira12,
  19. Mónica Marazuela13,
  20. Xavier Matias-Guiu14,
  21. Amparo Meoro-Avilés15,
  22. Ana Patiño-García16,
  23. Susana Pedrinaci17,
  24. Garcilaso Riesco-Eizaguirre18,
  25. Constantino Sábado-Álvarez19,
  26. Raquel Sáez-Villaverde20,
  27. Amaya Sainz de los Terreros21,
  28. Óscar Sanz Guadarrama22,
  29. Julia Sastre-Marcos23,
  30. Bartolomé Scolá-Yurrita24,
  31. Ángel Segura-Huerta25,
  32. Maria de la Soledad Serrano-Corredor26,
  33. María Rosa Villar-Vicente27,
  34. Cristina Rodríguez-Antona1,2,
  35. Esther Korpershoek28,
  36. Alberto Cascón1,2,
  37. Mercedes Robledo1,2
  1. 1Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain
  2. 2Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
  3. 3Department of Endocrinology, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
  4. 4Department of Endocrinology, Hospital Universitario Severo Ochoa, Madrid, Spain
  5. 5Department of Endocrinology, Hospital Universitario Puerta de Hierro, Madrid, Spain
  6. 6Department of Endocrinology, Hospital Universitario La Paz, Madrid, Spain
  7. 7Department of Endocrinology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
  8. 8Department of Endocrinology, Hospital Infanta Sofía, San Sebastián de los Reyes, Spain
  9. 9Department of Endocrinology, Hospital Universitario 12 de Octubre, Madrid, Spain
  10. 10Department of Endocrinology, Hospital Clínico San Carlos, Madrid, Spain
  11. 11Department of Endocrinology, Hospital El Bierzo, León, Spain
  12. 12Department of Endocrinology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
  13. 13Department of Endocrinology, Hospital Universitario de La Princesa, Instituto Princesa, Madrid, Spain
  14. 14Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida, Lleida, Spain
  15. 15Department of Endocrinology, Hospital General Universitario Reina Sofía, Murcia, Spain
  16. 16Department of Pediatrics and Clinical Genetics Unit, Clínica Universidad de Navarra, Navarra, Spain
  17. 17Department of Genetics, Hospital Universitario Virgen de las Nieves, Granada, Spain
  18. 18Department of Endocrinology, Hospital Universitario de Móstoles, Madrid, Spain
  19. 19Department of Pediatric Oncology and Hematology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
  20. 20Department of Genetics, Hospital Universitario Donostia, Gipuzkoa, Spain
  21. 21Department of Endocrinology, Complejo Hospitalario de Navarra, Navarra, Spain
  22. 22Department of General Surgery and Digestive Tract, Complejo Asistencial de León, León, Spain
  23. 23Department of Endocrinology, Hospital Virgen de la Salud—Complejo Hospitalario de Toledo, Toledo, Spain
  24. 24Department of Otorhinolaryngology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
  25. 25Genetic Counselling Cancer Unit, Hospital Universitari i Politecnic La Fe, Valencia, Spain
  26. 26Department of Endocrinology, Hospital General Universitario de Alicante, Alicante, Spain
  27. 27Department of Endocrinology, Hospital Universitario de Fuenlabrada, Madrid, Spain
  28. 28Erasmus Universitair Medisch Centrum Rotterdam, Rotterdam, The Netherlands
  1. Correspondence to Dr Mercedes Robledo, Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, Madrid 28029, Spain; mrobledo{at}


Background Nowadays, 65–80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source.

Methods The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL, the SDH genes, TMEM127, MAX and FH. 99 tumours from patients negative for germline screening were available and tested for RET, VHL, HRAS, EPAS1, MAX and SDHB.

Results Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p=6.62×10−10). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p=0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p=2.0×10−4 and p=0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS.

Conclusions We recommend prioritising testing for germline mutations in patients with HN-PGLs and T-PGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.

  • Cancer: endocrine
  • Endocrinology
  • Genetic screening/counselling
  • Paediatric oncology
  • Adrenal disorders

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