Molecular characterisation of renal cell carcinoma and related disorders

Over the last two decades genetic advances have provided novel insights into the molecular basis of familial and sporadic cancers and provided the basis for the development of novel therapeutic approaches. For example, the identification of the gene for von Hippel Lindau disease provided seminal insights into its role in most clear cell renal carcinomas (RCC) and led to new treatments for RCC. In this thesis I investigated three related genetic aspects of neoplasia. Firstly, I analyzed the results of genetic testing for inherited phaeochromocytoma and investigated how clinical features could be used to stratify patients and improve the cost effectiveness of genetic testing. Secondly, I sought to identify novel causes of inherited neoplasia. Through exome sequencing of familial RCC kindreds, \(CDKN2B\) was identified as a novel familial RCC gene. The role of \(CDKN2B\) mutations in neoplasia was evaluated in familial and sporadic RCC and phaeochromocytoma. \(In\) \(vitro\) assays confirmed that germline \(CDKN2B\) mutations associated with inherited RCC caused an abrogation of tumour suppressor function. Finally, I explored how a gene-based strategy might be used to identify novel therapeutic strategies, Thus, using a siRNA library screen, in RCC cells with inactivated \(VHL\), potential candidate targets (e.g. \({PLK1/STK}\)-\(10\)) were identified for selectively decreasing the viability of RCC cells with inactivated \(VHL\).