Maria Currás-Freixes1, Lucía Inglada-Pérez2, Veronika Mancikova1, Cristina Montero-Conde1, Rocío Letón1, Iñaki Comino-Méndez1, María Apellániz-Ruiz1, Lara Sánchez-Barroso1, Miguel Aguirre Sánchez-Covisa3, Victoria Alcázar4, Javier Aller5, Cristina Álvarez-Escolá6, Víctor M Andía-Melero7, Sharona Azriel-Mira8, María Calatayud-Gutiérrez9, José Ángel Díaz10, Alberto Díez-Hernández11, Cristina Lamas-Oliveira12, Mónica Marazuela13, Xavier Matias-Guiu14, Amparo Meoro-Avilés15, Ana Patiño-García16, Susana Pedrinaci17, Garcilaso Riesco-Eizaguirre18, Constantino Sábado-Álvarez19, Raquel Sáez-Villaverde20, Amaya Sainz de Los Terreros21, Óscar Sanz Guadarrama22, Julia Sastre-Marcos23, Bartolomé Scolá-Yurrita24, Ángel Segura-Huerta25, Maria de la Soledad Serrano-Corredor26, María Rosa Villar-Vicente27, Cristina Rodríguez-Antona2, Esther Korpershoek28, Alberto Cascón2, Mercedes Robledo2. 1. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain. 2. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain. 3. Department of Endocrinology, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain. 4. Department of Endocrinology, Hospital Universitario Severo Ochoa, Madrid, Spain. 5. Department of Endocrinology, Hospital Universitario Puerta de Hierro, Madrid, Spain. 6. Department of Endocrinology, Hospital Universitario La Paz, Madrid, Spain. 7. Department of Endocrinology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 8. Department of Endocrinology, Hospital Infanta Sofía, San Sebastián de los Reyes, Spain. 9. Department of Endocrinology, Hospital Universitario 12 de Octubre, Madrid, Spain. 10. Department of Endocrinology, Hospital Clínico San Carlos, Madrid, Spain. 11. Department of Endocrinology, Hospital El Bierzo, León, Spain. 12. Department of Endocrinology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain. 13. Department of Endocrinology, Hospital Universitario de La Princesa, Instituto Princesa, Madrid, Spain. 14. Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida, Lleida, Spain. 15. Department of Endocrinology, Hospital General Universitario Reina Sofía, Murcia, Spain. 16. Department of Pediatrics and Clinical Genetics Unit, Clínica Universidad de Navarra, Navarra, Spain. 17. Department of Genetics, Hospital Universitario Virgen de las Nieves, Granada, Spain. 18. Department of Endocrinology, Hospital Universitario de Móstoles, Madrid, Spain. 19. Department of Pediatric Oncology and Hematology, Hospital Universitari Vall d'Hebron, Barcelona, Spain. 20. Department of Genetics, Hospital Universitario Donostia, Gipuzkoa, Spain. 21. Department of Endocrinology, Complejo Hospitalario de Navarra, Navarra, Spain. 22. Department of General Surgery and Digestive Tract, Complejo Asistencial de León, León, Spain. 23. Department of Endocrinology, Hospital Virgen de la Salud-Complejo Hospitalario de Toledo, Toledo, Spain. 24. Department of Otorhinolaryngology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 25. Genetic Counselling Cancer Unit, Hospital Universitari i Politecnic La Fe, Valencia, Spain. 26. Department of Endocrinology, Hospital General Universitario de Alicante, Alicante, Spain. 27. Department of Endocrinology, Hospital Universitario de Fuenlabrada, Madrid, Spain. 28. Erasmus Universitair Medisch Centrum Rotterdam, Rotterdam, The Netherlands.
Abstract
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Maria Currás-Freixes; Elena Piñeiro-Yañez; Cristina Montero-Conde; María Apellániz-Ruiz; Bruna Calsina; Veronika Mancikova; Laura Remacha; Susan Richter; Tonino Ercolino; Natalie Rogowski-Lehmann; Timo Deutschbein; María Calatayud; Sonsoles Guadalix; Cristina Álvarez-Escolá; Cristina Lamas; Javier Aller; Julia Sastre-Marcos; Conxi Lázaro; Juan C Galofré; Ana Patiño-García; Amparo Meoro-Avilés; Judith Balmaña-Gelpi; Paz De Miguel-Novoa; Milagros Balbín; Xavier Matías-Guiu; Rocío Letón; Lucía Inglada-Pérez; Rafael Torres-Pérez; Juan M Roldán-Romero; Cristina Rodríguez-Antona; Stephanie M J Fliedner; Giuseppe Opocher; Karel Pacak; Esther Korpershoek; Ronald R de Krijger; Laurent Vroonen; Massimo Mannelli; Martin Fassnacht; Felix Beuschlein; Graeme Eisenhofer; Alberto Cascón; Fátima Al-Shahrour; Mercedes Robledo Journal: J Mol Diagn Date: 2017-05-25 Impact factor: 5.568
Authors: Pauline Romanet; Carole Guerin; Pascal Pedini; Wassim Essamet; Frédéric Castinetti; Fréderic Sebag; Philippe Roche; Alberto Cascon; Arthur S Tischler; Karel Pacak; Anne Barlier; David Taïeb Journal: Endocr Pathol Date: 2017-12 Impact factor: 3.943