Epigenetics of renal cell carcinoma the path towards new diagnostics and therapeutics.docVIP

Morris and Maher Genome Medicine 2010, 2:59 /content/2/9/59 REVIEW Epigenetics of renal cell carcinoma: the path towards new diagnostics and therapeutics Mark R Morris and Eamonn R Maher * 1,2 1,2,3 and activation of a wide repertoire of hypoxia response genes [7]. e frequency of VHL mutations in sporadic ccRCC has been reported to be as high as 75% (although VHL mutations are rare in non-clear-cell forms of RCC). In addition to VHL mutations, VHL allele loss of 3p25, resulting in biallelic VHL inactivation, is the most fre- quent copy number abnormality in ccRCC (as predicted by a classical ‘two hit’ model of tumorigenesis, where loss of the second allele of a key tumour suppressor is required for tumour formation to occur) [8,9]. Abstract Aberrant DNA methylation, in particular promoter hypermethylation and transcriptional silencing of tumor suppressor genes, has an important role in the development of many human cancers, including renal cell carcinoma (RCC). Indeed, apart from mutations in the well studied von Hippel-Lindau gene (VHL), the mutation frequency rates of known tumor suppressor genes in RCC are generally low, but the number of genes found to show frequent inactivation by promoter methylation in RCC continues to grow. Here, we review the genes identied as epigenetically silenced in RCC and their relationship to pathways of tumor development. Increased understanding of RCC epigenetics provides new insights into the molecular pathogenesis of RCC and opportunities for developing novel strategies for the diagnosis, prognosis and management of RCC. Although the VHL mutations in primary RCC were detected about 16 years ago, attempts to identify other frequently mutated RCC genes have been unsuccessful, with none of the thousands of genes tested so far mutated in over 15% of tumors [10]. TSG inactivation may result from genetic o