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.
- cancer: endocrine
- molecular genetics
- genetic epidemiology
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Contributors ERM conceived, designed and supervised the study. KAA collected the data and performed the Kaplan-Meier analysist. DBA and DEVP produced the in silico structural prediction analysis. DRB and ACA performed the retrospective cohort analysis calculations. The remaining authors clinically characterised the patients at their respective centres. All authors were involved in drafting the article or revising it critically for important intellectual content and in the final approval of the version to be submitted. KAA and ERM wrote the first draft of the paper and are responsible for the overall content as guarantors.
Funding 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 RCUK-CONFAP 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. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health.
Disclaimer The funding agencies had no role in study design, data collection or analysis or writing of the article.
Competing interests None declared.
Patient consent Obtained.
Ethics approval South Birmingham Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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