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

被引：186

作者：

Andrews, Katrina A. ^{[1
,2
,3
,4
]}

Ascher, David B. ^{[5
,6
]}

Pires, Douglas Eduardo Valente ^{[5
,7
]}

Barnes, Daniel R. ^{[8
]}

Vialard, Lindsey ^{[9
]}

Casey, Ruth T. ^{[1
,2
,3
,4
]}

Bradshaw, Nicola ^{[10
]}

Adlard, Julian ^{[11
]}

Aylwin, Simon ^{[12
]}

Brennan, Paul ^{[13
]}

Brewer, Carole ^{[14
]}

Cole, Trevor ^{[9
]}

Cook, Jackie A. ^{[15
]}

Davidson, Rosemarie ^{[10
]}

Donaldson, Alan ^{[16
]}

Fryer, Alan ^{[17
]}

Greenhalgh, Lynn ^{[17
]}

Hodgson, Shirley V. ^{[18
]}

Irving, Richard ^{[19
]}

Lalloo, Fiona ^{[20
]}

McConachie, Michelle ^{[21
]}

McConnell, Vivienne P. M. ^{[22
]}

Morrison, Patrick J. ^{[22
]}

Murday, Victoria ^{[10
]}

Park, Soo-Mi ^{[23
]}

Simpson, Helen L. ^{[24
]}

Snape, Katie ^{[18
]}

Stewart, Susan ^{[9
]}

Tomkins, Susan E. ^{[16
]}

Wallis, Yvonne ^{[9
]}

Izatt, Louise ^{[25
]}

Goudie, David ^{[21
]}

Lindsay, Robert S. ^{[26
]}

Perry, Colin G. ^{[26
]}

Woodward, Emma R.

Antoniou, Antonis C. ^{[8
]}

Maher, Eamonn R. ^{[1
,2
,3
,4
,24
]}

机构：

[1] Univ Cambridge, Dept Med Genet, Cambridge CB2 0QQ, England

[2] NIHR Cambridge Biomed Res Ctr, Cambridge, England

[3] Canc Res UK Cambridge Canc Ctr, Cambridge, England

[4] Cambridge Univ Hosp NHS Fdn Trust, Cambridge, England

[5] Univ Cambridge, Dept Biochem, Cambridge, England

[6] Univ Melbourne, Inst Bio21, Dept Biochem & Mol Biol, Melbourne, Vic, Australia

[7] Fundacao Oswaldo Cruz, Inst Rene Rachou, Belo Horizonte, MG, Brazil

[8] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[9] Birmingham Womens Hosp, West Midlands Reg Genet Serv, Birmingham, W Midlands, England

[10] Queen Elizabeth Univ Hosp, Dept Clin Genet, Glasgow, Lanark, Scotland

[11] St James Univ Hosp, Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England

[12] Kings Coll Hosp London, Dept Endocrinol, London, England

[13] Newcastle upon Tyne Hosp NHS Fdn Trust, Northern Genet Serv, Newcastle Upon Tyne, Tyne & Wear, England

[14] Royal Devon & Exeter Hosp, Peninsula Clin Genet Serv, Exeter, Devon, England

[15] Sheffield Childrens Hosp, Dept Clin Genet, Sheffield, S Yorkshire, England

[16] St Michaels Hosp, Dept Clin Genet, Bristol, Avon, England

[17] Liverpool Womens NHS Fdn Trust, Dept Clin Genet, Liverpool, Merseyside, England

[18] St Georges Univ London, Dept Med Genet, London, England

[19] Queen Elizabeth Hosp, Queen Elizabeth Med Ctr, Birmingham, W Midlands, England

[20] Cent Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Manchester Ctr Genom Med, Manchester, Lancs, England

[21] Ninewells Hosp & Med Sch, East Scotland Reg Genet Serv, Dundee, Scotland

[22] Belfast Hlth & Social Care Trust, Belfast City Hosp, Northern Ireland Reg Genet Serv, Belfast, Antrim, North Ireland

[23] Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Treatment Ctr, Dept Clin Genet, Cambridge, England

[24] Cambridge Univ Hosp NHS Fdn Trust, Inst Metab Sci, Wolfson Diabet & Endocrine Clin, Cambridge, England

[25] Guys Hosp, Dept Clin Genet, London, England

[26] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland

来源：

JOURNAL OF MEDICAL GENETICS | 2018年 / 55卷 / 06期

基金：

英国医学研究理事会; 欧洲研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

COMPLEX-II; MUTATION CARRIERS; MATERNAL TRANSMISSION; NECK PARAGANGLIOMA; PROTEIN STABILITY; PHEOCHROMOCYTOMA; PENETRANCE; SUSCEPTIBILITY; GENETICS; DELETION;

D O I：

10.1136/jmedgenet-2017-105127

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：384 / 394

页数：11

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