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

被引：173

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：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会; 欧洲研究理事会;

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

共 61 条

[1] [Anonymous], 2017, R LANG ENV STAT COMP
[2] Succinate dehydrogenase subunit B (SDHB) gene deletion associated with a composite paraganglioma/neuroblastoma
Armstrong, R.
Greenhalgh, K. L.
Rattenberry, E.
Judd, B.
Shukla, R.
Losty, P. D.
Maher, E. R.
[J]. JOURNAL OF MEDICAL GENETICS, 2009, 46 (03) : 215 - 216
[3] Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility
Astuti, D
Hart-Holden, N
Latif, F
Lalloo, F
Black, GC
Lim, C
Moran, A
Grossman, AB
Hodgson, SV
Freemont, A
Ramsden, R
Eng, C
Evans, DGR
Maher, ER
[J]. CLINICAL ENDOCRINOLOGY, 2003, 59 (06) : 728 - 733
[4] Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma
Astuti, D
Latif, F
Dallol, A
Dahia, PLM
Douglas, F
George, E
Sköldberg, F
Husebye, ES
Eng, C
Maher, ER
[J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 69 (01) : 49 - 54
[5] Evaluation of Association Methods for Analysing Modifiers of Disease Risk in Carriers of High-Risk Mutations
Barnes, Daniel R.
Lee, Andrew
Easton, Douglas F.
Antoniou, Antonis C.
[J]. GENETIC EPIDEMIOLOGY, 2012, 36 (03) : 274 - 291
[6] Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations
Bayley, Jean-Pierre
Oldenburg, Rogier A.
Nuk, Jennifer
Hoekstra, Attje S.
van der Meer, Conny A.
Korpershoek, Esther
McGillivray, Barbara
Corssmit, Eleonora P. M.
Dinjens, Winand N. M.
de Krijger, Ronald R.
Devilee, Peter
Jansen, Jeroen C.
Hes, Frederik J.
[J]. BMC MEDICAL GENETICS, 2014, 15
[7] The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients
Bayley, Jean-Pierre
Grimbergen, Anneliese Em
van Bunderen, Patrick A.
van der Wielen, Michiel
Kunst, Henricus P.
Lenders, Jacques W.
Jansen, Jeroen C.
Dullaart, Robin P. F.
Devilee, Peter
Corssmit, Eleonora P.
Vriends, Annette H.
Losekoot, Monique
Weiss, Marjan M.
[J]. BMC MEDICAL GENETICS, 2009, 10
[8] The SDH mutation database: an online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency
Bayley, JP
Devilee, P
Taschner, PEM
[J]. BMC MEDICAL GENETICS, 2005, 6
[9] An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma
Baysal, BE
Willett-Brozick, JE
Filho, PAA
Lawrence, EC
Myers, EN
Ferrell, RE
[J]. JOURNAL OF MEDICAL GENETICS, 2004, 41 (09) : 703 - 709
[10] Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma
Baysal, BE
Ferrell, RE
Willett-Brozick, JE
Lawrence, EC
Myssiorek, D
Bosch, A
van der Mey, A
Taschner, PEM
Rubinstein, WS
Myers, EN
Richard, CW
Cornelisse, CJ
Devilee, P
Devlin, B
[J]. SCIENCE, 2000, 287 (5454) : 848 - 851

← 1 2 3 4 5 6 7 →