1. ¹Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, The Medical School, Edgbaston, Birmingham B15 2TT, UK
2. ²Cancer Research UK Renal Molecular Oncology Research Group, University of Birmingham, The Medical School, Edgbaston, Birmingham B15 2TT, UK
3. ³Department of Clinical Genetics, Gothenburg University, Sahlgrenska University Hospital/Ostra, S-416 85 Gothenburg, Sweden
4. ⁴Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden
5. ⁵Medizinische Universitatsklinik, Hugstetter Str. 55, D-79106 Freiburg, Germany
6. ⁶Department of Paediatrics, Kuopio University Hospital, FIN-70211 Kuopio, Finland
7. ⁷Department of Pathology, Haartman-Institute, FIN-00014 University of Helsinki, Helsinki, Finland
8. ⁸Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, the Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
9. ⁹INSERM U393 Handicaps Génétique de l'Enfant, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75015 Paris, France

Correspondence: Professor ER Maher, E-mail: E.R.Maher@bham.ac.uk

Received 10 May 2004; Revised 31 August 2004; Accepted 2 September 2004; Published online 26 October 2004.

Abstract

Germline 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.