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

Abstract

BackgroundGermline 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.MethodsA 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.ResultsTumour 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%).ConclusionsOverall 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.

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

“…40 Males seem to be slightly more at risk than females of developing a PGL. 40,41 SDHB-related PGL/PCC are associated with a high risk of metastasis and poor prognosis. Earlier studies report a higher metastatic rate (31%-97%) [42][43][44][45] than more recent studies.…”

“…Penetrance of dif- Kaplan-Meier analysis showed an estimated risk for the combined manifestation of PCC, sympathetic PGL and HNPGL in non-index patients to be 22% at age 60. 40 In their retrospective cohort analysis (index and non-index patients) the penetrance was 24% at age 60 years. 40 Males seem to be slightly more at risk than females of developing a PGL.…”

“…40 In their retrospective cohort analysis (index and non-index patients) the penetrance was 24% at age 60 years. 40 Males seem to be slightly more at risk than females of developing a PGL. 40,41 SDHB-related PGL/PCC are associated with a high risk of metastasis and poor prognosis.…”

“…Earlier studies report a higher metastatic rate (31%-97%) [42][43][44][45] than more recent studies. 40 In a meta-analysis including 12 studies comprising both asymptomatic SDHB carriers and carriers with manifest non-metastatic disease, van Hulsteijn et al reported a metastatic rate of 17%. 46 The risk of metastasis in HNPGL in SDHB mutation carriers appears to be lower compared to PGL developing at other sites.…”

Paraganglioma of the tongue with SDHB gene mutation in a patient with Graves’ disease

“…It was identified a germline mutation in SDHB gene that has been described in Mediterranean population carrying a 45% of malignancy risk. 19 Germline mutations in SDHx are inherited in an autosomal dominant manner with an age-related penetrance. 1,7,8 Genetic testing should be performed in all PGLs.…”