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

Andrews, K. A. et al. (2018) Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. Journal of Medical Genetics, 55(6), pp. 384-394. (doi: 10.1136/jmedgenet-2017-105127) (PMID:29386252) (PMCID:PMC5992372)

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: Articles
• Additional Information: This work was supported by the East Anglian Foundation Programme (to KAA), the University of Cambridge (KAA), NIHR Cambridge Biomedical Research Centre (KAA and ERM), Cancer Research UK Cambridge Cancer Centre (ERM), European Research Council Advanced Researcher Award (ERM), British Heart Foundation (EM), NIHR Senior Investigator Award (ERM), Newton Fund RCUKCONFAP Grant awarded by The Medical Research Council (MRC), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) (to DEVP and DBA), NHMRC CJ Martin Fellowship (APP1072476) and Jack Brockhoff Foundation (JBF 4186, 2016) (to DBA), Instituto René Rachou (CPqRR/FIOCRUZ Minas) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (to DEVP), Health Research Board Ireland (RTC ) and Cancer Research – UK grant C12292/A20861 (to ACA). The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve.
• Keywords: Cancer: endocrine, genetic epidemiology, genetics, molecular genetics, oncology.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Lindsay, Dr Robert and Perry, Dr Colin and Bradshaw, Ms Nicola
• Authors: Andrews, K. A., Ascher, D. B., Pires, D. E. V., Barnes, D. R., Vialard, L., Casey, R. T., Bradshaw, N., Adlard, J., Aylwin, S., Brennan, P., Brewer, C., Cole, T., Cook, J. A., Davidson, R., Donaldson, A., Fryer, A., Greenhalgh, L., Hodgson, S. V., Irving, R., Lalloo, F., McConachie, M., McConnell, V. P.M., Morrison, P. J., Murday, V., Park, S.-M., Simpson, H. L., Snape, K., Stewart, S., Tomkins, S. E., Wallis, Y., Izatt, L., Goudie, D., Lindsay, R. S., Perry, C. G., Woodward, E. R., Antoniou, A. C., and Maher, E. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Journal of Medical Genetics
• Publisher: BMJ Publishing Group
• ISSN: 0022-2593
• ISSN (Online): 1468-6244
• Published Online: 31 January 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Journal of Medical Genetics 55(6): 384-394
• Publisher Policy: Reproduced under a Creative Commons License