Investigation of the role of SDHB inactivation in sporadic phaeochromocytoma and neuroblastoma
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AbstractGermline mutations in the succinate dehydrogenase (SDH) (mitochondrial respiratory chain complex II) subunit B gene, SDHB, cause susceptibility to head and neck paraganglioma and phaeochromocytoma. Previously, we did not identify somatic SDHB mutations in sporadic phaeochromocytoma, but SDHB maps to 1p36, a region of frequent loss of heterozygosity (LOH) in neuroblastoma as well. Hence, to evaluate SDHB as a candidate neuroblastoma tumour suppressor gene (TSG) we performed mutation analysis in 46 primary neuroblastomas by direct sequencing, but did not identify germline or somatic SDHB mutations. As TSGs such as RASSF1A are frequently inactivated by promoter region hypermethylation, we designed a methylation-sensitive PCR-based assay to detect SDHB promoter region methylation. In 21% of primary neuroblastomas and 32% of phaeochromocytomas (32%) methylated (and unmethylated) alleles were detected. Although promoter region methylation was also detected in two neuroblastoma cell lines, this was not associated with silencing of SDHB expression, and treatment with a demethylating agent (5-azacytidine) did not increase SDH activity. These findings suggest that although germline SDHB mutations are an important cause of phaeochromocytoma susceptibility, somatic inactivation of SDHB does not have a major role in sporadic neural crest tumours and SDHB is not the target of 1p36 allele loss in neuroblastoma and phaeochromocytoma. © 2004 Cancer Research UK.
CitationAstuti, D., Morris, M., Krona, C., Abel, F., Gentle, D., Martinsson, T., Kogner, P., Neumann, H. P. H., Voutilainen, R., Eng, C., Rustin, P., Latif, F. and Maher, E. R. (2004) Investigation of the role of SDHB inactivation in sporadic phaeochromocytoma and neuroblastoma, British Journal of Cancer (2004) 91, pp. 1835-1841.
JournalBritish Journal of Cancer
SponsorsThis work is supported by the British Heart Foundation (DA, FL, EM), Cancer Research UK (MM, FL, EM), Swedish Cancer Society, Swedish Children's Cancer Foundation (TM, PK), Deutsche Forchungsgemeinschaft Grant NE 571/5-2 and the Deutsche Krebshilfe Grant 70-3313-Ne 1 (HPH) and P30CA16058 from the National Cancer Institute, Bethesda, MD, USA (to The Ohio State University Comprehensive Cancer Center). CE is a recipient of the Doris Duke Distinguished Clinical Scientist Award.
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- Authors: Astuti D, Agathanggelou A, Honorio S, Dallol A, Martinsson T, Kogner P, Cummins C, Neumann HP, Voutilainen R, Dahia P, Eng C, Maher ER, Latif F
- Issue date: 2001 Nov 8
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- Authors: Benn DE, Croxson MS, Tucker K, Bambach CP, Richardson AL, Delbridge L, Pullan PT, Hammond J, Marsh DJ, Robinson BG
- Issue date: 2003 Mar 6
- Evaluation of a functional epigenetic approach to identify promoter region methylation in phaeochromocytoma and neuroblastoma.
- Authors: Margetts CD, Morris M, Astuti D, Gentle DC, Cascon A, McRonald FE, Catchpoole D, Robledo M, Neumann HP, Latif F, Maher ER
- Issue date: 2008 Sep
- Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma.
- Authors: Bayley JP, van Minderhout I, Weiss MM, Jansen JC, Oomen PH, Menko FH, Pasini B, Ferrando B, Wong N, Alpert LC, Williams R, Blair E, Devilee P, Taschner PE
- Issue date: 2006 Jan 11
- Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility.
- Authors: 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 DG, Maher ER
- Issue date: 2003 Dec