Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Hereditary Cancer in Clinical Practice
Published in: Hereditary Cancer in Clinical Practice 1/2016

Open Access 01-12-2016 | Research

Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients

Authors: Marc Bennedbæk, Maria Rossing, Åse K. Rasmussen, Anne-Marie Gerdes, Anne-Bine Skytte, Uffe B. Jensen, Finn C. Nielsen, Thomas v. O. Hansen

Published in: Hereditary Cancer in Clinical Practice | Issue 1/2016

Login to get access

Abstract

Background

Germline mutations in the succinate dehydrogenase complex genes SDHB, SDHC, and SDHD predispose to pheochromocytomas and paragangliomas. Here, we examine the SDHB, SDHC, and SDHD mutation spectrum in the Danish population by screening of 143 Danish pheochromocytoma and paraganglioma patients.

Methods

Mutational screening was performed by Sanger sequencing or next-generation sequencing. The frequencies of variants of unknown clinical significance, e.g. intronic, missense, and synonymous variants, were determined using the Exome Aggregation Consortium database, while the significance of missense mutations was predicted by in silico and loss of heterozygosity analysis when possible.

Results

We report 18 germline variants; nine in SDHB, six in SDHC, and three in SDHD. Of these 18 variants, eight are novel. We classify 12 variants as likely pathogenic/pathogenic, one as likely benign, and five as variants of unknown clinical significance.

Conclusions

Identifying and classifying SDHB, SDHC, and SDHD variants present in the Danish population will augment the growing knowledge on variants in these genes and may support future clinical risk assessments.
Literature
1.
Dahia PL. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat Rev Cancer. 2014;14:108–19.CrossRefPubMed
2.
Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol. 2015;11:101–11.CrossRefPubMed
3.
Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001;69:49–54.CrossRefPubMedPubMedCentral
4.
Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287:848–51.CrossRefPubMed
5.
6.
Castro-Vega LJ, Buffet A, de Cubas AA, et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet. 2014;23:2440–6.CrossRefPubMed
7.
Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43:663–7.CrossRefPubMed
8.
Kunst HP, Rutten MH, de Monnink J, et al. SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin Cancer Res. 2011;17:247–54.CrossRefPubMed
9.
Neumann HP, Berger DP, Sigmund G, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med. 1993;329:1531–8.CrossRefPubMed
10.
Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet. 2000;26:268–70.CrossRefPubMed
11.
12.
Smith DP, Eng C, Ponder BA. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes and Hirschsprung disease. J Cell Sci Suppl. 1994;18:43–9.CrossRefPubMed
13.
Viskochil D, Buchberg AM, Xu G, et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990;62:187–92.CrossRefPubMed
14.
Bardella C, Pollard PJ, Tomlinson I. SDH mutations in cancer. Biochim Biophys Acta. 2011;1807:1432–43.CrossRefPubMed
15.
Jain-Ghai S, Cameron JM, Al Maawali A, et al. Complex II deficiency--a case report and review of the literature. Am J Med Genet A. 2013;161A:285–94.CrossRefPubMed
16.
17.
Zhang L, Yu L, Yu CA. Generation of superoxide anion by succinate-cytochrome c reductase from bovine heart mitochondria. J Biol Chem. 1998;273:33972–6.CrossRefPubMed
18.
Ahlborn LB, Dandanell M, Steffensen AY, et al. Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic. Breast Cancer Res Treat. 2015;150:289–98.CrossRefPubMedPubMedCentral
19.
Lohmueller KE, Sparso T, Li Q, et al. Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes. Am J Hum Genet. 2013;93:1072–86.CrossRefPubMedPubMedCentral
20.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.CrossRefPubMedPubMedCentral
21.
McWhinney SR, Pilarski RT, Forrester SR, et al. Large germline deletions of mitochondrial complex II subunits SDHB and SDHD in hereditary paraganglioma. J Clin Endocrinol Metab. 2004;89:5694–9.CrossRefPubMed
22.
Cascon A, Montero-Conde C, Ruiz-Llorente S, et al. Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot? Genes Chromosomes Cancer. 2006;45:213–9.CrossRefPubMed
23.
Burnichon N, Rohmer V, Amar L, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009;94:2817–27.CrossRefPubMed
24.
Piccini V, Rapizzi E, Bacca A, et al. Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. Endocr Relat Cancer. 2012;19:149–55.CrossRefPubMed
25.
Sjursen W, Halvorsen H, Hofsli E, et al. Mutation screening in a Norwegian cohort with pheochromocytoma. Fam Cancer. 2013;12:529–35.CrossRefPubMed
26.
Burnichon N, Vescovo L, Amar L, et al. Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet. 2011;20:3974–85.CrossRefPubMed
27.
van Nederveen FH, Gaal J, Favier J, et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 2009;10:764–71.CrossRefPubMedPubMedCentral
28.
Fokkema IF, Taschner PE, Schaafsma GC, et al. LOVD v. 2.0: the next generation in gene variant databases. Hum Mutat. 2011;32:557–63.CrossRefPubMed
29.
Brouwers FM, Eisenhofer G, Tao JJ, et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006;91:4505–9.CrossRefPubMed
30.
Lima J, Feijao T, Ferreira da Silva A, et al. High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain: mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathological correlations. J Clin Endocrinol Metab. 2007;92:4853–64.CrossRefPubMed
31.
Pasini B, McWhinney SR, Bei T, et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008;16:79–88.CrossRefPubMed
32.
Neumann HP, Erlic Z, Boedeker CC, et al. Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res. 2009;69:3650–6.CrossRefPubMed
33.
Vandy FC, Sisk G, Berguer R. Synchronous carotid body and thoracic paraganglioma associated with a germline SDHC mutation. J Vasc Surg. 2011;53:805–7.CrossRefPubMed
34.
Panizza E, Ercolino T, Mori L, et al. Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. Hum Mol Genet. 2013;22:804–15.CrossRefPubMed
35.
Yu W, He X, Ni Y, et al. Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation. Hum Mol Genet. 2015;24:142–53.CrossRefPubMed
36.
Dannenberg H, Dinjens WN, Abbou M, et al. Frequent germ-line succinate dehydrogenase subunit D gene mutations in patients with apparently sporadic parasympathetic paraganglioma. Clin Cancer Res. 2002;8:2061–6.PubMed
37.
Schiavi F, Dematte S, Cecchini ME, et al. The endemic paraganglioma syndrome type 1: origin, spread, and clinical expression. J Clin Endocrinol Metab. 2012;97:E637–41.CrossRefPubMed
38.
Taschner PE, Jansen JC, Baysal BE, et al. Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene. Genes Chromosomes Cancer. 2001;31:274–81.CrossRefPubMed
39.
Badenhop RF, Jansen JC, Fagan PA, et al. The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features. J Med Genet. 2004;41:e99.CrossRefPubMedPubMedCentral
40.
Douwes Dekker PB, Corver WE, Hogendoorn PC, et al. Multiparameter DNA flow-sorting demonstrates diploidy and SDHD wild-type gene retention in the sustentacular cell compartment of head and neck paragangliomas: chief cells are the only neoplastic component. J Pathol. 2004;202:456–62.CrossRefPubMed
41.
Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–66.CrossRefPubMed
42.
Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004;292:943–51.CrossRefPubMed
43.
Evenepoel L, Papathomas TG, Krol N, et al. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med. 2015;17:610–20.CrossRefPubMed
44.
Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003;63:5615–21.PubMed
45.
Perren A, Barghorn A, Schmid S, et al. Absence of somatic SDHD mutations in sporadic neuroendocrine tumors and detection of two germline variants in paraganglioma patients. Oncogene. 2002;21:7605–8.CrossRefPubMed
46.
Riemann K, Sotlar K, Kupka S, et al. Chromosome 11 monosomy in conjunction with a mutated SDHD initiation codon in nonfamilial paraganglioma cases. Cancer Genet Cytogenet. 2004;150:128–35.CrossRefPubMed
47.
Kytola S, Nord B, Elder EE, et al. Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas. Genes Chromosomes Cancer. 2002;34:325–32.CrossRefPubMed
48.
Castellano M, Mori L, Giacche M, et al. Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients. Ann NY Acad Sci. 2006;1073:156–65.CrossRefPubMed
49.
Antonello M, Piazza M, Menegolo M, et al. Role of the genetic study in the management of carotid body tumor in paraganglioma syndrome. Eur J Vasc Endovasc Surg. 2008;36:517–9.CrossRefPubMed
50.
Benn DE, Gimenez-Roqueplo AP, Reilly JR, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006;91:827–36.CrossRefPubMed
51.
Braun S, Riemann K, Kupka S, et al. Active succinate dehydrogenase (SDH) and lack of SDHD mutations in sporadic paragangliomas. Anticancer Res. 2005;25:2809–14.PubMed
52.
Fish JH, Klein-Weigel P, Biebl M, et al. Systematic screening and treatment evaluation of hereditary neck paragangliomas. Head Neck. 2007;29:864–73.CrossRefPubMed
53.
Milunsky JM, Maher TA, Michels VV, et al. Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma. Am J Med Genet. 2001;100:311–4.CrossRefPubMed
Metadata
Title
Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients
Authors
Marc Bennedbæk
Maria Rossing
Åse K. Rasmussen
Anne-Marie Gerdes
Anne-Bine Skytte
Uffe B. Jensen
Finn C. Nielsen
Thomas v. O. Hansen
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Hereditary Cancer in Clinical Practice / Issue 1/2016
Electronic ISSN: 1897-4287
DOI
https://doi.org/10.1186/s13053-016-0053-6

Other articles of this Issue 1/2016

Hereditary Cancer in Clinical Practice 1/2016 Go to the issue

Research

Recurrent mutations of BRCA1, BRCA2 and PALB2 in the population of breast and ovarian cancer patients in Southern Poland

Research

Intensive breast screening in BRCA2 mutation carriers is associated with reduced breast cancer specific and all cause mortality

Research

Prognostic factors in Polish patients with BRCA1-dependent ovarian cancer

Research

Implications of using whole genome sequencing to test unselected populations for high risk breast cancer genes: a modelling study

Case report

A novel deleterious c.2656G>T MSH2 germline mutation in a Pakistani family with a phenotypic overlap of hereditary breast and ovarian cancer and Lynch syndrome

Research

Assessing biases of information contained in pedigrees for the classification of BRCA-genetic variants: a study arising from the ENIGMA analytical working group
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits