SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

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

Andrews, KA; Ascher, DB; Pires, DEV; Barnes, DR; Vialard, L; Casey, RT; Bradshaw, N; Adlard, J; Aylwin, S; Brennan, P; et al. Andrews, KA; Ascher, DB; Pires, DEV; Barnes, DR; Vialard, L; Casey, RT; Bradshaw, N; Adlard, J; Aylwin, S; Brennan, P; Brewer, C; Cole, T; Cook, JA; Davidson, R; Donaldson, A; Fryer, A; Greenhalgh, L; Hodgson, SV; Irving, R; Lalloo, F; McConachie, M; McConnell, VPM; Morrison, PJ; Murday, V; Park, S-M; Simpson, HL; Snape, K; Stewart, S; Tomkins, SE; Wallis, Y; Izatt, L; Goudie, D; Lindsay, RS; Perry, CG; Woodward, ER; Antoniou, AC; Maher, ER (2018) Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet, 55 (6). pp. 384-394. ISSN 1468-6244 https://doi.org/10.1136/jmedgenet-2017-105127
SGUL Authors: Hodgson, Shirley Victoria Snape, Katie Mairwen Greenwood

[img]
Preview
PDF Published Version
Available under License Creative Commons Attribution.

Download (1MB) | Preview

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.

Item Type: Article
Additional Information: 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/ © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Keywords: cancer: endocrine, genetic epidemiology, genetics, molecular genetics, oncology, Genetics & Heredity, 06 Biological Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: J Med Genet
ISSN: 1468-6244
Language: eng
Dates:
DateEvent
June 2018Published
31 January 2018Published Online
8 January 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDBritish Heart Foundationhttp://dx.doi.org/10.13039/501100000274
UNSPECIFIEDMedical Research Councilhttp://dx.doi.org/10.13039/501100000265
JBF 4186, 2016Jack Brockhoff FoundationUNSPECIFIED
APP1072476National Health and Medical Research Councilhttp://dx.doi.org/10.13039/501100000925
C12292/A20861Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
PubMed ID: 29386252
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109608
Publisher's version: https://doi.org/10.1136/jmedgenet-2017-105127

Actions (login required)

Edit Item Edit Item