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JAMA Oncol. 2017 Sep 1;3(9):1204-1212. doi: 10.1001/jamaoncol.2017.0223.

Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.

Author information

1
Department of Medicine II, Freiburg University Medical Center, Albert-Ludwigs University, Freiburg, Germany.
2
Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
3
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
4
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
5
Second Department of Medicine, Semmelweis University, Budapest, Hungary.
6
Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
7
Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
8
Department of Surgery, University of Lübeck, Lübeck, Germany.
9
Department of Nephrology and General Medicine, University Medical Center, Albert-Ludwigs University, Freiburg, Germany.
10
Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital Stockholm, Stockholm, Sweden.
11
Department of Medicine, Endocrinology, and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
12
Institute of Nuclear Medicine, University Hospital, Bern, Switzerland.
13
Department of Hypertension, Institute of Cardiology, Warsaw, Poland.
14
Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.
15
Center for Endocrine Tumors, Hamburg, Germany.
16
Department of Endocrinology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
17
Department of Endocrinology, Helios Klinikum, Erfurt, Germany.
18
Department of Endocrinology, Ludwigs-Maximilians University of Munich, Munich, Germany.
19
Department of Surgery, City Hospital, Starnberg, Germany.
20
Department of Otorhinolaryngology, University of Erlangen, Erlangen, Germany.
21
Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany.
22
Department of Otolaryngology, University of Cologne, Cologne, Germany.
23
Department of Otorhinolaryngology, University of Regensburg, Regensburg, Germany.
24
Division of Endocrine Surgery, Department of General Surgery, Ege University, Izmir, Turkey.
25
Department of Otolaryngology, HELIOS Hanseklinikum Stralsund, Stralsund, Germany.
26
Department of Endocrinology, University of Nancy, Nancy, France.
27
Department of Surgery and Center of Minimally Invasive Surgery, Kliniken Essen-Mitte, Essen, Germany.
28
Department of Surgery, Region Östergötland, Linköping, Sweden.
29
Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
30
Section for Preventive Medicine, University Medical Center, Albert-Ludwigs University, Freiburg, Germany.

Abstract

Importance:

Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking.

Objective:

To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes.

Design, Setting, and Patients:

This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes.

Main Outcomes and Measures:

Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized.

Results:

Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001).

Conclusions and Relevance:

The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

PMID:
28384794
PMCID:
PMC5824290
DOI:
10.1001/jamaoncol.2017.0223
[Indexed for MEDLINE]
Free PMC Article

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