Andrews, Katrina A, Ascher, David B, Pires, Douglas Eduardo Valente, Barnes, Daniel R, Vialard, Lindsey, Casey, Ruth T, Bradshaw, Nicola, Adlard, Julian, Aylwin, Simon, Brennan, Paul et al (show 27 more authors)
(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.
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Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD.pdf - Published version Download (1MB) | Preview |
Abstract
<h4>Background</h4>Germline pathogenic variants in <i>SDHB/SDHC</i>/<i>SDHD</i> 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 <i>SDHB/SDHC</i>/<i>SDHD</i> mutation carriers.<h4>Methods</h4>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 <i>SDHB/SDHC</i>/<i>SDHD</i> (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses.<h4>Results</h4>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 <i>SDHD:</i>p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising <i>SDHB</i> missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in <i>SDHB</i> and (paternally inherited) <i>SDHD</i> 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 <i>SDHB</i> mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for <i>SDHB</i> 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%).<h4>Conclusions</h4>Overall risks of clinically apparent tumours for <i>SDHB</i> 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 <i>SDHB/SDHC</i>/<i>SDHD</i> mutation carriers.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Paraganglioma, Pheochromocytoma, Adrenal Gland Neoplasms, Succinate Dehydrogenase, Membrane Proteins, Risk Factors, Age Factors, Sex Characteristics, Genotype, Heterozygote, Germ-Line Mutation, Mutation, Missense, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genetic Association Studies, Kaplan-Meier Estimate |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 05 Jun 2019 09:40 |
| Last Modified: | 19 Jan 2023 00:41 |
| DOI: | 10.1136/jmedgenet-2017-105127 |
| Open Access URL: | http://doi.org/10.1136/jmedgenet-2017-105127 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3044547 |
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