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

35 Citations (Scopus)
130 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

Fingerprint

Succinate Dehydrogenase
Genetic Association Studies
Mutation
Penetrance
Genes
Neoplasms
Paraganglioma
Pheochromocytoma
Germ-Line Mutation
Kaplan-Meier Estimate
Genetic Testing
Missense Mutation
Individuality
Computer Simulation
Counseling
Cohort Studies
Genotype
Phenotype

Keywords

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

Cite this

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 ; Brewer, Carole ; Cole, Trevor ; Cook, Jackie A. ; Davidson, Rosemarie ; Donaldson, Alan ; Fryer, Alan ; Greenhalgh, Lynn ; Hodgson, Shirley V. ; Irving, Richard ; Lalloo, Fiona ; McConachie, Michelle ; McConnell, Vivienne P. M. ; Morrison, Patrick J. ; Murday, Victoria ; Park, Soo-Mi ; Simpson, Helen L. ; Snape, Katie ; Stewart, Susan ; Tomkins, Susan E. ; Wallis, Yvonne ; Izatt, Louise ; Goudie, David ; Lindsay, Robert S. ; Perry, Colin G. ; Woodward, Emma R. ; Antoniou, Antonis C. ; Maher, Eamonn R. / Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. In: Journal of Medical Genetics. 2018 ; Vol. 55. pp. 384-394.
@article{4074a5cc6d7e462f98021c8443fcbed3,
title = "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",
author = "Andrews, {Katrina A.} and Ascher, {David B.} and Pires, {Douglas Eduardo Valente} and Barnes, {Daniel R.} and Lindsey Vialard and Casey, {Ruth T.} and Nicola Bradshaw and Julian Adlard and Simon Aylwin and Paul Brennan and Carole Brewer and Trevor Cole and Cook, {Jackie A.} and Rosemarie Davidson and Alan Donaldson and Alan Fryer and Lynn Greenhalgh and Hodgson, {Shirley V.} and Richard Irving and Fiona Lalloo and Michelle McConachie and McConnell, {Vivienne P. M.} and Morrison, {Patrick J.} and Victoria Murday and Soo-Mi Park and Simpson, {Helen L.} and Katie Snape and Susan Stewart and Tomkins, {Susan E.} and Yvonne Wallis and Louise Izatt and David Goudie and Lindsay, {Robert S.} and Perry, {Colin G.} and Woodward, {Emma R.} and Antoniou, {Antonis C.} and Maher, {Eamonn R.}",
note = "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), Funda{\cc}{\~a}o de Amparo {\`a} 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 Ren{\'e} Rachou (CPqRR/FIOCRUZ Minas) and Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico (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.",
year = "2018",
month = "6",
doi = "10.1136/jmedgenet-2017-105127",
language = "English",
volume = "55",
pages = "384--394",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",

}

Andrews, KA, Ascher, DB, Pires, DEV, Barnes, DR, Vialard, L, Casey, RT, Bradshaw, N, Adlard, J, Aylwin, S, Brennan, P, Brewer, C, Cole, T, Cook, JA, Davidson, R, Donaldson, A, Fryer, A, Greenhalgh, L, Hodgson, SV, Irving, R, Lalloo, F, McConachie, M, McConnell, VPM, Morrison, PJ, Murday, V, Park, S-M, Simpson, HL, Snape, K, Stewart, S, Tomkins, SE, Wallis, Y, Izatt, L, Goudie, D, Lindsay, RS, Perry, CG, Woodward, ER, Antoniou, AC & Maher, ER 2018, 'Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD', Journal of Medical Genetics, vol. 55, pp. 384-394. https://doi.org/10.1136/jmedgenet-2017-105127

Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. / 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; Brewer, Carole; Cole, Trevor; Cook, Jackie A.; Davidson, Rosemarie; Donaldson, Alan; Fryer, Alan; Greenhalgh, Lynn; Hodgson, Shirley V.; Irving, Richard; Lalloo, Fiona; McConachie, Michelle; McConnell, Vivienne P. M.; Morrison, Patrick J.; Murday, Victoria; Park, Soo-Mi; Simpson, Helen L.; Snape, Katie; Stewart, Susan; Tomkins, Susan E.; Wallis, Yvonne; Izatt, Louise; Goudie, David; Lindsay, Robert S.; Perry, Colin G.; Woodward, Emma R.; Antoniou, Antonis C.; Maher, Eamonn R. (Lead / Corresponding author).

In: Journal of Medical Genetics, Vol. 55, 06.2018, p. 384-394.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD

AU - Andrews, Katrina A.

AU - Ascher, David B.

AU - Pires, Douglas Eduardo Valente

AU - Barnes, Daniel R.

AU - Vialard, Lindsey

AU - Casey, Ruth T.

AU - Bradshaw, Nicola

AU - Adlard, Julian

AU - Aylwin, Simon

AU - Brennan, Paul

AU - Brewer, Carole

AU - Cole, Trevor

AU - Cook, Jackie A.

AU - Davidson, Rosemarie

AU - Donaldson, Alan

AU - Fryer, Alan

AU - Greenhalgh, Lynn

AU - Hodgson, Shirley V.

AU - Irving, Richard

AU - Lalloo, Fiona

AU - McConachie, Michelle

AU - McConnell, Vivienne P. M.

AU - Morrison, Patrick J.

AU - Murday, Victoria

AU - Park, Soo-Mi

AU - Simpson, Helen L.

AU - Snape, Katie

AU - Stewart, Susan

AU - Tomkins, Susan E.

AU - Wallis, Yvonne

AU - Izatt, Louise

AU - Goudie, David

AU - Lindsay, Robert S.

AU - Perry, Colin G.

AU - Woodward, Emma R.

AU - Antoniou, Antonis C.

AU - Maher, Eamonn R.

N1 - 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.

PY - 2018/6

Y1 - 2018/6

N2 - 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.

AB - 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.

KW - cancer: endocrine

KW - genetic epidemiology

KW - genetics

KW - molecular genetics

KW - oncology

UR - http://www.scopus.com/inward/record.url?scp=85048367906&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2017-105127

DO - 10.1136/jmedgenet-2017-105127

M3 - Article

C2 - 29386252

VL - 55

SP - 384

EP - 394

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

ER -