Colorectal cancer (CRC) is one of the most common cancers in both males and females, and it is perhaps the best understood of all epithelial tumors in terms of its molecular origin. Yet, despite large amount of work that has concentrated on understanding of colon tumorigenesis, we still do not know the full complement of molecular lesions that are individually necessary – and together sufficient – to cause colorectal cancer. Neither do we understand why some specific mutations that are relatively rare in other tumors (e.g. loss of the APC tumor suppressor) are extremely common in colorectal cancer. We propose here to use the tools of systems biology to develop a quantitative and comprehensive model of colorectal tumorigenesis. The model will include a “wiring diagram” that identifies cell-type specific and oncogenic pathways that contribute to colon tumorigenesis, and explains in molecular detail how a genotype of an individual CRC leads to activation of downstream genes that drive uncontrolled cell growth. This model will subsequently be used to find novel therapeutic targets, to guide genetic screening to identify individuals with elevated risk for developing CRC, and to classify patients into molecular subgroups to select the treatment combination which is optimal for each patient (personalized medicine). The specific objectives of the SYSCOL project are:1. Identify genetic markers for individual risk using genotyping and sequencing of germline DNA from sporadic and familial CRC cases and controls2. Identify genes and regulatory elements that contribute to colorectal cancer cell growth3. Use data from Aims 1-2 to develop a quantitative model for colorectal tumorigenesis4. Apply the model for identification of high-risk individuals, for molecular classification of the disease, and for identification of novel molecular treatment targets