Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients.
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.
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
Maria
M
Currás-Freixes
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
Lucía
L
Inglada-Pérez
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
Veronika
V
Mancikova
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
Cristina
C
Montero-Conde
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
Rocío
R
Letón
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
Iñaki
I
Comino-Méndez
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
María
M
Apellániz-Ruiz
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
Lara
L
Sánchez-Barroso
Department of Endocrinology, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain.
Miguel
M
Aguirre Sánchez-Covisa
Department of Endocrinology, Hospital Universitario Severo Ochoa, Madrid, Spain.
Victoria
V
Alcázar
Department of Endocrinology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
Javier
J
Aller
Department of Endocrinology, Hospital Universitario La Paz, Madrid, Spain.
Cristina
C
Álvarez-Escolá
Department of Endocrinology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Víctor M
VM
Andía-Melero
Department of Endocrinology, Hospital Infanta Sofía, San Sebastián de los Reyes, Spain.
Sharona
S
Azriel-Mira
Department of Endocrinology, Hospital Universitario 12 de Octubre, Madrid, Spain.
María
M
Calatayud-Gutiérrez
Department of Endocrinology, Hospital Clínico San Carlos, Madrid, Spain.
José Ángel
JÁ
Díaz
Department of Endocrinology, Hospital El Bierzo, León, Spain.
Alberto
A
Díez-Hernández
Department of Endocrinology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
Cristina
C
Lamas-Oliveira
Department of Endocrinology, Hospital Universitario de La Princesa, Instituto Princesa, Madrid, Spain.
Mónica
M
Marazuela
Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida, Lleida, Spain.
Xavier
X
Matias-Guiu
Department of Endocrinology, Hospital General Universitario Reina Sofía, Murcia, Spain.
Amparo
A
Meoro-Avilés
Department of Pediatrics and Clinical Genetics Unit, Clínica Universidad de Navarra, Navarra, Spain.
Ana
A
Patiño-García
Department of Genetics, Hospital Universitario Virgen de las Nieves, Granada, Spain.
Susana
S
Pedrinaci
Department of Endocrinology, Hospital Universitario de Móstoles, Madrid, Spain.
Garcilaso
G
Riesco-Eizaguirre
Department of Pediatric Oncology and Hematology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Constantino
C
Sábado-Álvarez
Department of Genetics, Hospital Universitario Donostia, Gipuzkoa, Spain.
Raquel
R
Sáez-Villaverde
Department of Endocrinology, Complejo Hospitalario de Navarra, Navarra, Spain.
Amaya
A
Sainz de Los Terreros
Department of General Surgery and Digestive Tract, Complejo Asistencial de León, León, Spain.
Óscar
Ó
Sanz Guadarrama
Department of Endocrinology, Hospital Virgen de la Salud-Complejo Hospitalario de Toledo, Toledo, Spain.
Julia
J
Sastre-Marcos
Department of Otorhinolaryngology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Bartolomé
B
Scolá-Yurrita
Genetic Counselling Cancer Unit, Hospital Universitari i Politecnic La Fe, Valencia, Spain.
Ángel
Á
Segura-Huerta
Department of Endocrinology, Hospital General Universitario de Alicante, Alicante, Spain.
Maria de la Soledad
Mde L
Serrano-Corredor
Department of Endocrinology, Hospital Universitario de Fuenlabrada, Madrid, Spain.
María Rosa
MR
Villar-Vicente
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
Cristina
C
Rodríguez-Antona
Erasmus Universitair Medisch Centrum Rotterdam, Rotterdam, The Netherlands.
Esther
E
Korpershoek
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
Alberto
A
Cascón
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
Mercedes
M
Robledo
D000310:Adrenal Gland Neoplasms / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D055317:Evidence-Based Practice; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010235:Paraganglioma / Q000175:diagnosis / Q000235:genetics*; D010673:Pheochromocytoma / Q000175:diagnosis / Q000235:genetics*; D013899:Thoracic Neoplasms / Q000175:diagnosis / Q000235:genetics*
Adrenal disorders; Cancer: endocrine; Endocrinology; Genetic screening/counselling; Paediatric oncology