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

Publication Date:
2018-05-26
Publisher:
BMJ Publishing Group
Print ISSN:
0022-2593
Electronic ISSN:
1468-6244
Topics:
Medicine
Keywords:
Open access, Molecular genetics
Published by:
http://www.bmj.com/
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autor Andrews, K. A., Ascher, D. B., Pires, D. E. V., Barnes, D. R., Vialard, L., Casey, R. T., Bradshaw, N., Adlard, J., Aylwin, S., Brennan, P., Brewer, C., Cole, T., Cook, J. A., Davidson, R., Donaldson, A., Fryer, A., Greenhalgh, L., hodgson, S. V., Irving, R., Lalloo, F., McConachie, M., McConnell, V. P. M., Morrison, P. J., Murday, V., Park, S.-M., Simpson, H. L., Snape, K., Stewart, S., Tomkins, S. E., Wallis, Y., Izatt, L., Goudie, D., Lindsay, R. S., Perry, C. G., Woodward, E. R., Antoniou, A. C., Maher, E. R.
beschreibung 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.
citation_standardnr 6267984
datenlieferant ipn_articles
feed_id 5627
feed_publisher BMJ Publishing Group
feed_publisher_url http://www.bmj.com/
insertion_date 2018-05-26
journaleissn 1468-6244
journalissn 0022-2593
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher BMJ Publishing Group
quelle Journal of Medical Genetics
relation http://jmg.bmj.com/cgi/content/short/55/6/384?rss=1
schlagwort Open access, Molecular genetics
search_space articles
shingle_author_1 Andrews, K. A., Ascher, D. B., Pires, D. E. V., Barnes, D. R., Vialard, L., Casey, R. T., Bradshaw, N., Adlard, J., Aylwin, S., Brennan, P., Brewer, C., Cole, T., Cook, J. A., Davidson, R., Donaldson, A., Fryer, A., Greenhalgh, L., hodgson, S. V., Irving, R., Lalloo, F., McConachie, M., McConnell, V. P. M., Morrison, P. J., Murday, V., Park, S.-M., Simpson, H. L., Snape, K., Stewart, S., Tomkins, S. E., Wallis, Y., Izatt, L., Goudie, D., Lindsay, R. S., Perry, C. G., Woodward, E. R., Antoniou, A. C., Maher, E. R.
shingle_author_2 Andrews, K. A., Ascher, D. B., Pires, D. E. V., Barnes, D. R., Vialard, L., Casey, R. T., Bradshaw, N., Adlard, J., Aylwin, S., Brennan, P., Brewer, C., Cole, T., Cook, J. A., Davidson, R., Donaldson, A., Fryer, A., Greenhalgh, L., hodgson, S. V., Irving, R., Lalloo, F., McConachie, M., McConnell, V. P. M., Morrison, P. J., Murday, V., Park, S.-M., Simpson, H. L., Snape, K., Stewart, S., Tomkins, S. E., Wallis, Y., Izatt, L., Goudie, D., Lindsay, R. S., Perry, C. G., Woodward, E. R., Antoniou, A. C., Maher, E. R.
shingle_author_3 Andrews, K. A., Ascher, D. B., Pires, D. E. V., Barnes, D. R., Vialard, L., Casey, R. T., Bradshaw, N., Adlard, J., Aylwin, S., Brennan, P., Brewer, C., Cole, T., Cook, J. A., Davidson, R., Donaldson, A., Fryer, A., Greenhalgh, L., hodgson, S. V., Irving, R., Lalloo, F., McConachie, M., McConnell, V. P. M., Morrison, P. J., Murday, V., Park, S.-M., Simpson, H. L., Snape, K., Stewart, S., Tomkins, S. E., Wallis, Y., Izatt, L., Goudie, D., Lindsay, R. S., Perry, C. G., Woodward, E. R., Antoniou, A. C., Maher, E. R.
shingle_author_4 Andrews, K. A., Ascher, D. B., Pires, D. E. V., Barnes, D. R., Vialard, L., Casey, R. T., Bradshaw, N., Adlard, J., Aylwin, S., Brennan, P., Brewer, C., Cole, T., Cook, J. A., Davidson, R., Donaldson, A., Fryer, A., Greenhalgh, L., hodgson, S. V., Irving, R., Lalloo, F., McConachie, M., McConnell, V. P. M., Morrison, P. J., Murday, V., Park, S.-M., Simpson, H. L., Snape, K., Stewart, S., Tomkins, S. E., Wallis, Y., Izatt, L., Goudie, D., Lindsay, R. S., Perry, C. G., Woodward, E. R., Antoniou, A. C., Maher, E. R.
shingle_catch_all_1 Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD
Open access, Molecular genetics
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.
Andrews, K. A., Ascher, D. B., Pires, D. E. V., Barnes, D. R., Vialard, L., Casey, R. T., Bradshaw, N., Adlard, J., Aylwin, S., Brennan, P., Brewer, C., Cole, T., Cook, J. A., Davidson, R., Donaldson, A., Fryer, A., Greenhalgh, L., hodgson, S. V., Irving, R., Lalloo, F., McConachie, M., McConnell, V. P. M., Morrison, P. J., Murday, V., Park, S.-M., Simpson, H. L., Snape, K., Stewart, S., Tomkins, S. E., Wallis, Y., Izatt, L., Goudie, D., Lindsay, R. S., Perry, C. G., Woodward, E. R., Antoniou, A. C., Maher, E. R.
BMJ Publishing Group
0022-2593
00222593
1468-6244
14686244
shingle_catch_all_2 Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD
Open access, Molecular genetics
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.
Andrews, K. A., Ascher, D. B., Pires, D. E. V., Barnes, D. R., Vialard, L., Casey, R. T., Bradshaw, N., Adlard, J., Aylwin, S., Brennan, P., Brewer, C., Cole, T., Cook, J. A., Davidson, R., Donaldson, A., Fryer, A., Greenhalgh, L., hodgson, S. V., Irving, R., Lalloo, F., McConachie, M., McConnell, V. P. M., Morrison, P. J., Murday, V., Park, S.-M., Simpson, H. L., Snape, K., Stewart, S., Tomkins, S. E., Wallis, Y., Izatt, L., Goudie, D., Lindsay, R. S., Perry, C. G., Woodward, E. R., Antoniou, A. C., Maher, E. R.
BMJ Publishing Group
0022-2593
00222593
1468-6244
14686244
shingle_catch_all_3 Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD
Open access, Molecular genetics
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.
Andrews, K. A., Ascher, D. B., Pires, D. E. V., Barnes, D. R., Vialard, L., Casey, R. T., Bradshaw, N., Adlard, J., Aylwin, S., Brennan, P., Brewer, C., Cole, T., Cook, J. A., Davidson, R., Donaldson, A., Fryer, A., Greenhalgh, L., hodgson, S. V., Irving, R., Lalloo, F., McConachie, M., McConnell, V. P. M., Morrison, P. J., Murday, V., Park, S.-M., Simpson, H. L., Snape, K., Stewart, S., Tomkins, S. E., Wallis, Y., Izatt, L., Goudie, D., Lindsay, R. S., Perry, C. G., Woodward, E. R., Antoniou, A. C., Maher, E. R.
BMJ Publishing Group
0022-2593
00222593
1468-6244
14686244
shingle_catch_all_4 Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD
Open access, Molecular genetics
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.
Andrews, K. A., Ascher, D. B., Pires, D. E. V., Barnes, D. R., Vialard, L., Casey, R. T., Bradshaw, N., Adlard, J., Aylwin, S., Brennan, P., Brewer, C., Cole, T., Cook, J. A., Davidson, R., Donaldson, A., Fryer, A., Greenhalgh, L., hodgson, S. V., Irving, R., Lalloo, F., McConachie, M., McConnell, V. P. M., Morrison, P. J., Murday, V., Park, S.-M., Simpson, H. L., Snape, K., Stewart, S., Tomkins, S. E., Wallis, Y., Izatt, L., Goudie, D., Lindsay, R. S., Perry, C. G., Woodward, E. R., Antoniou, A. C., Maher, E. R.
BMJ Publishing Group
0022-2593
00222593
1468-6244
14686244
shingle_title_1 Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD
shingle_title_2 Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD
shingle_title_3 Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD
shingle_title_4 Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD
timestamp 2025-06-30T23:35:08.362Z
titel Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD
titel_suche Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD
topic WW-YZ
uid ipn_articles_6267984