The overall aim of this proposed project is to discovery new colorectal cancer (CRC) susceptibility genes to better understand the colorectal carcinogenesis process and improve the molecular diagnosis the affected families.CRC is one of the most important causes of morbidity and mortality in occidental countries. An early diagnosis of CRC as well as clinical surveillance of those with an increased risk to develop a CRC leads to an important decrease of CRC morbidity and mortality. Genetic diagnosis is a powerful tool to detect at risk patients, and although some genes have been demonstrated to cause CRC, they explain only a small proportion of cases. On these bases, a better understanding of the genetic contribution to CRC is necessary to achieve a meaningful impact on the disease. Here we propose a trans-Atlantic collaborative project to find new CRC susceptibility genes.Our first aim will be to identify new highly penetrant CRC susceptibility genes and variants using an exome-wide approach. Recent studies have demonstrated the feasibility of whole-exome sequencing (WES) as a powerful discovery tool for germline mutations in other familial cancers. By accurately selecting the families to be studied we expect to increase the gene identification rate. To this aim, we will restrict our WES analysis to highly enriched familial cases from two populations with an already demonstrated founder character (Québec –Canada– and Catalonia –Spain–).Given the recent evidences of the involvement of two spindle-assembly checkpoint (SAC) genes (BUB1B and BUB1) to hereditary colorectal carcinogenesis, our second aim is to identify new moderately penetrant CRC susceptibility genes and/or variants that are involved in the SAC pathway. From previous evidences we hypothesise that diminished expression of SAC genes may lead to carcinogenesis. To test subtle expression changes we will measure the allele-specific expression in nine SAC genes in a case-control study design.