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TUMOUR RISKS AND GENOTYPE-PHENOTYPE CORRELATIONS ASSOCIATED WITH GERMLINE VARIANTS IN SUCCINATE DEHYDROGENASE SUBUNIT GENES SDHB, SDHC AND SDHD
Andrews, Katrina A. et al. | Data do documento: 2018
Autor(es)
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.
Afiliação
Department of Medical Genetics. University of Cambridge. Cambridge, UK / NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre. Cambridge, UK / Cambridge University Hospitals NHS Foundation Trust. Cambridge, UK.
Department of Biochemistry. University of Cambridge, Cambridge, UK/Department of Biochemistry and Molecular Biology. Bio21 Institute. University of Melbourne. Melbourne, Victoria, Australia.
Department of Biochemistry. University of Cambridge, Cambridge, UK / Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.
Department of Public Health and Primary Care. University of Cambridge. Cambridge, UK.
West Midlands Regional Genetics service. Birmingham Women’s Hospital. Birmingham, UK.
Department of Medical Genetics. University of Cambridge. Cambridge, UK / NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre. Cambridge, UK / Cambridge University Hospitals NHS Foundation Trust. Cambridge, UK.
Department of Clinical Genetics. Queen Elizabeth University Hospital. Glasgow, UK.
Yorkshire Regional Genetics Service. St. James’s University Hospital. Leeds, UK.
Department of Endocrinology. King’s College Hospital. London, UK.
Northern Genetics Service. Newcastle upon Tyne Hospitals NHS Foundation Trust. Newcastle upon Tyne, UK.
Peninsula Clinical Genetics Service. Royal Devon & Exeter Hospital. Exeter, UK.
West Midlands Regional Genetics service. Birmingham Women’s Hospital. Birmingham, UK.
Department of Clinical Genetics. Sheffield Children’s Hospital. Sheffield, UK.
Department of Clinical Genetics. Queen Elizabeth University Hospital. Glasgow, UK.
Department of Clinical Genetics. St Michael’s Hospital. Bristol, UK.
Department of Clinical Genetics. Liverpool Women’s NHS Foundation Trust. Liverpool, UK.
Department of Clinical Genetics. Liverpool Women’s NHS Foundation Trust. Liverpool, UK.
Department of Medical Genetics. St. George’s University of London. London, UK.
Queen Elizabeth Medical Centre. Queen Elizabeth Hospital. Birmingham, UK.
Manchester Centre for Genomic Medicine. St Mary’s Hospital. Central Manchester University Hospitals NHS Foundation Trust. Manchester, UK.
East of Scotland Regional Genetics Service. Ninewells Hospital and Medical School. Dundee, UK.
Northern Ireland Regional Genetics Service. Belfast City Hospital. Belfast Health & Social Care Trust. Belfast, UK.
Northern Ireland Regional Genetics Service. Belfast City Hospital. Belfast Health & Social Care Trust. Belfast, UK.
Department of Clinical Genetics. Queen Elizabeth University Hospital. Glasgow, UK.
Department of Clinical Genetics. Addenbrooke’s Treatment Centre. Cambridge University Hospitals NHS Foundation Trust. Cambridge, UK.
The Wolfson Diabetes and Endocrine Clinic. Institute of Metabolic Science. Cambridge University Hospitals NHS Foundation Trust. Cambridge, UK.
Department of Medical Genetics. St. George’s University of London. London, UK.
West Midlands Regional Genetics service. Birmingham Women’s Hospital. Birmingham, UK.
Department of Clinical Genetics. St Michael’s Hospital. Bristol, UK.
West Midlands Regional Genetics service. Birmingham Women’s Hospital. Birmingham, UK.
Department of Clinical Genetics. Guy’s Hospital, London, UK.
East of Scotland Regional Genetics Service. Ninewells Hospital and Medical School. Dundee, UK.
Institute of Cardiovascular & Medical Sciences. University of Glasgow. Glasgow, Scotland, UK.
Institute of Cardiovascular & Medical Sciences. University of Glasgow. Glasgow, Scotland, UK.
Manchester Centre for Genomic Medicine. St Mary’s Hospital. Central Manchester University Hospitals NHS Foundation Trust. Manchester, UK.
Department of Public Health and Primary Care. University of Cambridge. Cambridge, UK.
Department of Medical Genetics. University of Cambridge. Cambridge, UK / NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre. Cambridge, UK /Cambridge University Hospitals NHS Foundation Trust. Cambridge, UK / The Wolfson Diabetes and Endocrine Clinic. Institute of Metabolic Science. Cambridge University Hospitals NHS Foundation Trust. Cambridge, UK.
Resumo em Inglês
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.
Palavras-chave
Cancer
Palavras-chave em inglês
Cancer endocrine
Genetic epidemiology
Genetics
Molecular genetics
Oncology Drivers
Drug expenditure
Immunosuppressants
Trends
 
Editor
Taylor & Francis
Referência
ANDREWS, Katrina A et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. Journal of Medical Genetics, v. 55, n. 6, p. 384-394, 2018.
DOI
10.1136/jmedgenet-2017-105127
ISSN
0022-2593