Background: Malignant transformation of phaeochromocytomas/paragangliomas PC/PGL occurs in 10% of patients and prognosis is poor with a 5-year survival of <50%. SDHB gene mutations are associated with an increased risk of malignancy as up to 50% of patients with malignant PC have been found to carry hereditary germ line mutations in SDHB. Current treatment strategies have limited success in malignant disease. Our hypothesis is that methylation changes associated with SDHB inactivation can be characterised to guide better treatment strategies. Hypermethylation of gene promoter regions leads to reduced expression of that gene thus reduced expression of MGMT due to hypermethylation detected by immunohistochemical analysis of tumour tissue could be used as a biomarker to predict malignancy associated with SDHB mutations. Furthermore drug targeting of this epigenetic aberration may prove successful in the treatment of malignant disease. Aims: 1. Investigate patterns of MGMT gene methylation in SDHB related tumours. 2. Investigate the use of MGMT expression as a biomarker. 3. Investigate the response of tumours with known SDHB mutations and MGMT promoter hypermethylation to an alkylating agent Temozolomide, with proven efficacy in tumours with MGMT hypermethylation. Design: The study is a cohort study of a database of 800 patients with identified SDH mutations and will involve further prospective recruitment through identified pathways. Methods: A database and biobank of >800 UK SDHB/C/D mutation carriers has been established. For patients who developed a tumour (~400) paraffin embedded tissue and, in cases, frozen tumour samples. Tumour samples (initially 48-50) will be analysed specifically for MGMT promoter methylation and a subset will undergo comprehensive genome-wide methylation analysis. The MGMT methylation status will be correlated with clinical characteristics, to establish utility as a prognostic biomarker. In parallel, genome-wide DNA methylation profiling will identify additional candidate methylation biomarkers. Normal adrenal tissue will be used as control.
