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J Med Genet. 2015 Oct;52(10):647-56. doi: 10.1136/jmedgenet-2015-103218. Epub 2015 Aug 12.

Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients.

Author information

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.

KEYWORDS:

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

PMID:
26269449
DOI:
10.1136/jmedgenet-2015-103218
[Indexed for MEDLINE]

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