| Author | Andrews, Katrina A. | |
| Author | Ascher, David B. | |
| Author | Pires, Douglas Eduardo Valente | |
| Author | Barnes, Daniel R. | |
| Author | Vialard, Lindsey | |
| Author | Casey, Ruth T. | |
| Author | Bradshaw, Nicola | |
| Author | Adlard, Julian | |
| Author | Aylwin, Simon | |
| Author | Brennan, Paul | |
| Author | Brewer, Carole | |
| Author | Cole, Trevor | |
| Author | Cook, Jackie A. | |
| Author | Davidson, Rosemarie | |
| Author | Donaldson, Alan | |
| Author | Fryer, Alan | |
| Author | Greenhalgh, Lynn | |
| Author | Hodgson, Shirley V. | |
| Author | Irving, Richard | |
| Author | Lalloo, Fiona | |
| Author | McConachie, Michelle | |
| Author | McConnell, Vivienne P. M. | |
| Author | Morrison, Patrick J. | |
| Author | Murday, Victoria | |
| Author | Park, Soo-Mi | |
| Author | Simpson, Helen L. | |
| Author | Snape, Katie | |
| Author | Stewart, Susan | |
| Author | Tomkins, Susan E. | |
| Author | Wallis, Yvonne | |
| Author | Izatt, Louise | |
| Author | Goudie, David | |
| Author | Lindsay, Robert S. | |
| Author | Perry, Colin G. | |
| Author | Woodward, Emma R. | |
| Author | Antoniou, Antonis C. | |
| Author | Maher, Eamonn R. | |
| Access date | 2019-07-02T12:37:02Z | |
| Available date | 2019-07-02T12:37:02Z | |
| Document date | 2018 | |
| Citation | 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. | pt_BR |
| ISSN | 0022-2593 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/33770 | |
| Language | eng | pt_BR |
| Publisher | Taylor & Francis | pt_BR |
| Rights | restricted access | pt_BR |
| Subject in Portuguese | Cancer | pt_BR |
| Title | Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD | pt_BR |
| Type | Article | |
| DOI | 10.1136/jmedgenet-2017-105127 | |
| 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. | pt_BR |
| Affilliation | 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. | pt_BR |
| Affilliation | Department of Biochemistry. University of Cambridge, Cambridge, UK/Department of Biochemistry and Molecular Biology. Bio21 Institute. University of Melbourne. Melbourne, Victoria, Australia. | pt_BR |
| Affilliation | Department of Biochemistry. University of Cambridge, Cambridge, UK / Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil. | pt_BR |
| Affilliation | Department of Public Health and Primary Care. University of Cambridge. Cambridge, UK. | pt_BR |
| Affilliation | West Midlands Regional Genetics service. Birmingham Women’s Hospital. Birmingham, UK. | pt_BR |
| Affilliation | 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. | pt_BR |
| Affilliation | Department of Clinical Genetics. Queen Elizabeth University Hospital. Glasgow, UK. | pt_BR |
| Affilliation | Yorkshire Regional Genetics Service. St. James’s University Hospital. Leeds, UK. | pt_BR |
| Affilliation | Department of Endocrinology. King’s College Hospital. London, UK. | pt_BR |
| Affilliation | Northern Genetics Service. Newcastle upon Tyne Hospitals NHS Foundation Trust. Newcastle upon Tyne, UK. | pt_BR |
| Affilliation | Peninsula Clinical Genetics Service. Royal Devon & Exeter Hospital. Exeter, UK. | pt_BR |
| Affilliation | West Midlands Regional Genetics service. Birmingham Women’s Hospital. Birmingham, UK. | pt_BR |
| Affilliation | Department of Clinical Genetics. Sheffield Children’s Hospital. Sheffield, UK. | pt_BR |
| Affilliation | Department of Clinical Genetics. Queen Elizabeth University Hospital. Glasgow, UK. | pt_BR |
| Affilliation | Department of Clinical Genetics. St Michael’s Hospital. Bristol, UK. | pt_BR |
| Affilliation | Department of Clinical Genetics. Liverpool Women’s NHS Foundation Trust. Liverpool, UK. | pt_BR |
| Affilliation | Department of Clinical Genetics. Liverpool Women’s NHS Foundation Trust. Liverpool, UK. | pt_BR |
| Affilliation | Department of Medical Genetics. St. George’s University of London. London, UK. | pt_BR |
| Affilliation | Queen Elizabeth Medical Centre. Queen Elizabeth Hospital. Birmingham, UK. | pt_BR |
| Affilliation | Manchester Centre for Genomic Medicine. St Mary’s Hospital. Central Manchester University Hospitals NHS Foundation Trust. Manchester, UK. | pt_BR |
| Affilliation | East of Scotland Regional Genetics Service. Ninewells Hospital and Medical School. Dundee, UK. | pt_BR |
| Affilliation | Northern Ireland Regional Genetics Service. Belfast City Hospital. Belfast Health & Social Care Trust. Belfast, UK. | pt_BR |
| Affilliation | Northern Ireland Regional Genetics Service. Belfast City Hospital. Belfast Health & Social Care Trust. Belfast, UK. | pt_BR |
| Affilliation | Department of Clinical Genetics. Queen Elizabeth University Hospital. Glasgow, UK. | pt_BR |
| Affilliation | Department of Clinical Genetics. Addenbrooke’s Treatment Centre. Cambridge University Hospitals NHS Foundation Trust. Cambridge, UK. | pt_BR |
| Affilliation | The Wolfson Diabetes and Endocrine Clinic. Institute of Metabolic Science. Cambridge University Hospitals NHS Foundation Trust. Cambridge, UK. | pt_BR |
| Affilliation | Department of Medical Genetics. St. George’s University of London. London, UK. | pt_BR |
| Affilliation | West Midlands Regional Genetics service. Birmingham Women’s Hospital. Birmingham, UK. | pt_BR |
| Affilliation | Department of Clinical Genetics. St Michael’s Hospital. Bristol, UK. | pt_BR |
| Affilliation | West Midlands Regional Genetics service. Birmingham Women’s Hospital. Birmingham, UK. | pt_BR |
| Affilliation | Department of Clinical Genetics. Guy’s Hospital, London, UK. | pt_BR |
| Affilliation | East of Scotland Regional Genetics Service. Ninewells Hospital and Medical School. Dundee, UK. | pt_BR |
| Affilliation | Institute of Cardiovascular & Medical Sciences. University of Glasgow. Glasgow, Scotland, UK. | pt_BR |
| Affilliation | Institute of Cardiovascular & Medical Sciences. University of Glasgow. Glasgow, Scotland, UK. | pt_BR |
| Affilliation | Manchester Centre for Genomic Medicine. St Mary’s Hospital. Central Manchester University Hospitals NHS Foundation Trust. Manchester, UK. | pt_BR |
| Affilliation | Department of Public Health and Primary Care. University of Cambridge. Cambridge, UK. | pt_BR |
| Affilliation | 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. | pt_BR |
| Subject | Cancer endocrine | pt_BR |
| Subject | Genetic epidemiology | pt_BR |
| Subject | Genetics | pt_BR |
| Subject | Molecular genetics | pt_BR |
| Subject | Oncology Drivers | pt_BR |
| Subject | Drug expenditure | pt_BR |
| Subject | Immunosuppressants | pt_BR |
| Subject | Trends | pt_BR |
| Embargo date | 2025-01-01 | |
