"Cancer susceptibility genes involved in Mendelian inherited forms of colorectal cancer (CRC) (e.g., Lynch Syndrome) may account for only 5% of all CRC cases. However, increased cancer risk because of a positive family history may vary from 25 up to 40%, and the genetic basis for this familial aggregation remains largely unknown. Recently, high-resolution genomic strategies have revealed an unprecedented form of structural variation of the genome in the normal population, including copy number variants (CNV) and insertion-deletion polymorphisms (indels), which could predispose and influence on the progression of the disease. Using an array of genomic approaches and next-generation sequencing-based techniques, this proposal aims to discern the role of structural variants of the genome in the susceptibility and tumorigenesis in families with high risk of CRC, and to provide insights into how genome-wide copy number analysis can be used as a strategy to identify novel cancer-predisposing genes and mechanisms. In addition, based on gene expression profiling, we will interrogate the function of genes involved in CNVs and their consequences on gene expression in CRC cells. Furthermore, it is possible that CNV profiles and other genetic variants are associated with clinical conditions. This study will infer the genetic causes and mechanisms that lead to drug resistance in CRC patients. Using whole exome-sequencing, we will determine whether patients with responding and non-responding colorectal tumors to chemoradiotherapy treatment (e.g., 5-fluorouracil) show a different distribution of mutations, in their germline and somatically, and as a consequence which cellular pathways result commonly afflicted. Thus, this project will generate a landscape of genetic alterations associated with predisposition, tumor progression, and treatment response in colorectal cancer, which lately will lead to a better understanding of this disease and bring chances to an individualized medicine"