Tumour risks and genotype–phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes  SDHB ,  SDHC  and  SDHD

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Abstract

Background

Germline pathogenic variants in SDHB/SDHC/ SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype–phenotype correlations in a large cohort of SDHB/SDHC/ SDHD mutation carriers.

Methods

A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/ SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses.

Results

Tumour risks analysis provided novel penetrance estimates and genotype–phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%).

Conclusions

Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype–tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/ SDHD mutation carriers.

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Most cited references 48

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DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach

Douglas Pires, David B. Ascher, Tom Blundell (2014)

Cancer genome and other sequencing initiatives are generating extensive data on non-synonymous single nucleotide polymorphisms (nsSNPs) in human and other genomes. In order to understand the impacts of nsSNPs on the structure and function of the proteome, as well as to guide protein engineering, accurate in silicomethodologies are required to study and predict their effects on protein stability. Despite the diversity of available computational methods in the literature, none has proven accurate and dependable on its own under all scenarios where mutation analysis is required. Here we present DUET, a web server for an integrated computational approach to study missense mutations in proteins. DUET consolidates two complementary approaches (mCSM and SDM) in a consensus prediction, obtained by combining the results of the separate methods in an optimized predictor using Support Vector Machines (SVM). We demonstrate that the proposed method improves overall accuracy of the predictions in comparison with either method individually and performs as well as or better than similar methods. The DUET web server is freely and openly available at http://structure.bioc.cam.ac.uk/duet.

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Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.

B E Baysal, R Ferrell, J Willett-Brozick … (2000)

Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood. Analysis of families carrying the PGL1 gene, described here, revealed germ line mutations in the SDHD gene on chromosome 11q23. SDHD encodes a mitochondrial respiratory chain protein-the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS). In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology.

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Crystal structure of mitochondrial respiratory membrane protein complex II.

Yujia Zhai, George Xu, Xia Huo … (2005)

The mitochondrial respiratory Complex II or succinate:ubiquinone oxidoreductase (SQR) is an integral membrane protein complex in both the tricarboxylic acid cycle and aerobic respiration. Here we report the first crystal structure of Complex II from porcine heart at 2.4 A resolution and its complex structure with inhibitors 3-nitropropionate and 2-thenoyltrifluoroacetone (TTFA) at 3.5 A resolution. Complex II is comprised of two hydrophilic proteins, flavoprotein (Fp) and iron-sulfur protein (Ip), and two transmembrane proteins (CybL and CybS), as well as prosthetic groups required for electron transfer from succinate to ubiquinone. The structure correlates the protein environments around prosthetic groups with their unique midpoint redox potentials. Two ubiquinone binding sites are discussed and elucidated by TTFA binding. The Complex II structure provides a bona fide model for study of the mitochondrial respiratory system and human mitochondrial diseases related to mutations in this complex.

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Author and article information

Journal

Journal ID (nlm-ta): J Med Genet

Journal ID (iso-abbrev): J. Med. Genet

Journal ID (hwp): jmedgenet

Journal ID (publisher-id): jmg

Title: Journal of Medical Genetics

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0022-2593

ISSN (Electronic): 1468-6244

Publication date (Print): June 2018

Publication date (Electronic): 31 January 2018

Volume: 55

Issue: 6

Pages: 1-11

Affiliations

[1 ] departmentDepartment of Medical Genetics , University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre and Cambridge University Hospitals NHS Foundation Trust , Cambridge, UK

[2 ] departmentDepartment of Biochemistry , University of Cambridge , Cambridge, UK

[3 ] departmentDepartment of Biochemistry and Molecular Biology , Bio21 Institute, University of Melbourne , Melbourne, Victoria, Australia

[4 ] departmentInstituto René Rachou , Fundação Oswaldo Cruz , Belo Horizonte, Brazil

[5 ] departmentDepartment of Public Health and Primary Care , University of Cambridge , Cambridge, UK

[6 ] departmentWest Midlands Regional Genetics service , Birmingham Women’s Hospital , Birmingham, UK

[7 ] departmentDepartment of Clinical Genetics , Queen Elizabeth University Hospital , Glasgow, UK

[8 ] departmentYorkshire Regional Genetics Service , St. James’s University Hospital , Leeds, UK

[9 ] departmentDepartment of Endocrinology , King’s College Hospital , London, UK

[10 ] departmentNorthern Genetics Service , Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne, UK

[11 ] departmentPeninsula Clinical Genetics Service , Royal Devon & Exeter Hospital , Exeter, UK

[12 ] departmentDepartment of Clinical Genetics , Sheffield Children’s Hospital , Sheffield, UK

[13 ] departmentDepartment of Clinical Genetics , St Michael’s Hospital , Bristol, UK

[14 ] departmentDepartment of Clinical Genetics , Liverpool Women’s NHS Foundation Trust , Liverpool, UK

[15 ] departmentDepartment of Medical Genetics , St. George’s University of London , London, UK

[16 ] departmentQueen Elizabeth Medical Centre , Queen Elizabeth Hospital , Birmingham, UK

[17 ] departmentManchester Centre for Genomic Medicine , St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust , Manchester, UK

[18 ] departmentEast of Scotland Regional Genetics Service , Ninewells Hospital and Medical School , Dundee, UK

[19 ] departmentNorthern Ireland Regional Genetics Service , Belfast City Hospital, Belfast Health & Social Care Trust , Belfast, UK

[20 ] departmentDepartment of Clinical Genetics , Addenbrooke’s Treatment Centre, Cambridge University Hospitals NHS Foundation Trust , Cambridge, UK

[21 ] departmentThe Wolfson Diabetes and Endocrine Clinic, Institute of Metabolic Science , Cambridge University Hospitals NHS Foundation Trust , Cambridge, UK

[22 ] departmentDepartment of Clinical Genetics , Guy’s Hospital , London, UK

[23 ] departmentInstitute of Cardiovascular & Medical Sciences , University of Glasgow , Glasgow, Scotland

Author notes

[Correspondence to ] Professor Eamonn R Maher, Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK; erm1000@ 123456medschl.cam.ac.uk

Author information

Douglas Eduardo Valente Pires http://orcid.org/0000-0002-3004-2119

Eamonn R Maher http://orcid.org/0000-0002-6226-6918

Article

Publisher ID: jmedgenet-2017-105127

DOI: 10.1136/jmedgenet-2017-105127

PMC ID: 5992372

PubMed ID: 29386252

SO-VID: e1eb0775-481c-4cef-9e96-b8b210730a5e

License:

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

History

Date received : 23 October 2017

Date revision received : 05 January 2018

Date accepted : 08 January 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000272, National Institute for Health Research;

Funded by: FundRef http://dx.doi.org/10.13039/501100001590, Health Research Board;

Funded by: FundRef http://dx.doi.org/10.13039/501100000289, Cancer Research UK;

Funded by: FundRef http://dx.doi.org/10.13039/100010663, H2020 European Research Council;

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ScienceOpen disciplines: Genetics

Keywords: cancer: endocrine,genetics,molecular genetics,oncology,genetic epidemiology

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ScienceOpen disciplines: Genetics

Keywords: cancer: endocrine, genetics, molecular genetics, oncology, genetic epidemiology

Tumour risks and genotype–phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD

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