Aberrant DNA methylation is the most common molecular lesion of the cancer cell. Neither gene mutation nor cytogenetic abnormalities are as common in human tumours as DNA methylation alterations. The stability of our genome and correct gene expression is maintained to a great extent thanks to a perfectly preestablished pattern of DNA methylation and histone modifications. In cancer this idealistic scenario breaks down due to an interesting phenomenon whereby the regulatory regions (CpG islands) of certain tumour suppressor genes become hypermethylated, inactivating the gene as a consequence, whilst a wave of hypomethylation occurs in the genome. Indeed, CpG island promoter hypermethylation has a tumour-type-specific pattern, where each gene tends to be methylated in the cancer cells driven from a particular tissue, but not from others.
It is also widely accepted that the multiprotein complex associated with the methylated DNA is also crucially involved in the repression of gene expression. This complex contains methyl-CpG binding proteins (MBDs), histone deacetylases (HDAC), histone methyltransferases (HMT) and DNA methyltransferases (DNMT) which co-operate and reinforce the gene silencing through chromatin compactation. Another aspect crucial for the interest of epigenetics in cancer is that promoter hypermethylation of the CpG island of tumours suppressor genes occurs early in tumorigenesis. Furthermore, it has been extensively reported that CpG promoter hypermethylation can be used as predictor of cancer behaviour and a predictor of response to treatment.
This characteristics makes promoter hypermethylation combined with the epigenetic associated proteins profile, a potential biomarker for early detection of cancer and for the individualization of cancer treatment.
Although great efforts are being done these days to improve early detection of cancer; the complex nature of neoplastic transformation requires greater understanding of the mechanisms underlying tumor suppressor gene silencing by hypermethylation. To achieve this goal; we are going to use a novel technique based in chromatin immunoprecipitation, the Methylated DNA Immunoprecipitation (MeDIP) technique. MeDIP is a quick, easy and sensitive technique which allows to identify new targets of aberrant methylation in cancer. This tool combined with standard large-scale analysis of existing DNA microarrays will allow us the screening of a large set of tumour samples; and will permit us the use of epigenetic markers in a clinical setting. MeDIP technique would easily permit to obtain an epigenomic profile which will be used to personalize cancer treatment and to find new targets for early detection of cancer. The aims of our proposal are of fundamental interest not only to the research community but also of great interest for improving the health condition within the wider European community.