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

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.

Keywords: cancer: endocrine; genetic epidemiology; genetics; molecular genetics; oncology.

Figure 1

Penetrance of for clinically diagnosed disease in proband and non-proband SDHB, SDHC and SDHD mutation carriers with 95% CI shaded. HNPGL, head and neck paraganglioma; PPGL, phaeochromocytoma and paraganglioma.

Figure 2

Penetrance of clinical disease in SDHB mutation carriers by age 60 years, as calculated by different statistical techniques and in different subpopulations. HNPGL,  head and neck paraganglioma; PPGL, phaeochromocytoma and paraganglioma; RCC, renal cell carcinoma.

Figure 3

(A) The isoleucine reside at position 127 of SDHB is buried in the middle of the structure, making a network of strong intramolecular hydrophobic interactions. Mutation to serine would introduce a polar residue and disrupt all of these important contacts. (B) One of three iron–sulphur clusters in SDHB, coordinated by four cysteine residues. Four of these (Cys98, Cys101, Cys113 and Cys196) are mutated in our cohort.

Figure 4

Penetrance of clinical disease in proband and non-proband SDHD p.Pro81Leu mutation carriers versus all other SDHD mutation carriers with 95% CI marked. P values are for the log-rank test comparing the survival distributions of SDHD p.Pro81Leu and all other SDHD mutation carriers. HNPGL, head and neck paraganglioma; PPGL, phaeochromocytoma and paraganglioma.

Figure 5

Penetrance of clinical disease in SDHB missense mutation carrier probands, split by with more stabilising (more negative) and less destabilising (less negative) DUET scores. The maximally selected rank statistics from the ‘maxstat’ R package was used to find the optimum cutpoint for DUET score, and the number of probands in the DUET score groups for each analysis is displayed in ‘Number at risk’ tables below each plot. The optimum cutpoints for DUET score were −1.21 for PPGL risk and for PPGL/HNPGL risk, −0.88 for HNPGL risk and −1.02 for malignancy risk. HNPGL, head and neck paraganglioma; PPGL, phaeochromocytoma and paraganglioma.