MicroRNAs are small non-coding RNAs involved in cell homeostasis and carcinogenesis. MicroRNA deregulation is associated with colorectal cancer (CRC) progression. My study proposes to identify genetic and epigenetic events leading to microRNAs deregulation and use them as targets for drug development. My research proposal will address two important questions. First it will assess the contribution of genetic and epigenetic events in controlling microRNA genes and cancer phenotype. Second it will define synthetic lethal interaction between microRNA genes aberration and kinase genes in order to define novel target for therapy.Mutations and promoter methylation of microRNA genes and microRNA processing genes will be analyzed by massive parallel sequencing in a first cohort of CRC. Mathematical and in vitro analysis will be performed to test whether a mutation is a driver or passenger one. The frequency of driver mutations and promoter methylation will be confirmed in a large case-control study encompassing 2500 CRC patients. Mutational and methylation status will be matched with clinical-pathological features in order to detect correlations with clinical outcome. In order to translate my findings into drug development, genetic aberration in microRNA genes will be reproduced in CRC cell lines. Isogenic cell lines harboring the wild type or the mutant allele will be tested for cell viability in a parallel RNAi screening using siRNA libraries targeting kinase. Protein kinases are important mediators of microRNA function. More importantly, catalytic inhibitors of kinase can be easily developed making them attractive targets for synthetic lethality screening and drug development.