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

Katrina A. Andrews, David B. Ascher, Douglas Eduardo Valente Pires, Daniel R. Barnes, Lindsey Vialard, Ruth T. Casey, Nicola Bradshaw, Julian Adlard, Simon Aylwin, Paul Brennan, Carole Brewer, Trevor Cole, Jackie A. Cook, Rosemarie Davidson, Alan Donaldson, Alan Fryer, Lynn Greenhalgh, Shirley V. Hodgson, Richard Irving, Fiona LallooMichelle McConachie, Vivienne P. M. McConnell, Patrick J. Morrison, Victoria Murday, Soo-Mi Park, Helen L. Simpson, Katie Snape, Susan Stewart, Susan E. Tomkins, Yvonne Wallis, Louise Izatt, David Goudie, Robert S. Lindsay, Colin G. Perry, Emma R. Woodward, Antonis C. Antoniou, Eamonn R. Maher

Research output: Contribution to journalArticle

46 Citations (Scopus)
165 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)384-394
Number of pages11
JournalJournal of Medical Genetics
Volume55
Early online date31 Jan 2018
DOIs
Publication statusPublished - Jun 2018

Keywords

  • cancer: endocrine
  • genetic epidemiology
  • genetics
  • molecular genetics
  • oncology

Fingerprint Dive into the research topics of 'Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes <i>SDHB, SDHC</i> and <i>SDHD</i>'. Together they form a unique fingerprint.

  • Cite this

    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., ... Maher, E. R. (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, 384-394. https://doi.org/10.1136/jmedgenet-2017-105127