Early detection is crucial for the outcome of most cancers. Prevention of cancer development is even more desirable. To facilitate these ultimate goals we aim to construct a comprehensive view of the stepwise process through which common human cancers, such as colorectal cancer, arise. In particular, we aim to identify novel mechanisms of cancer susceptibility by focusing on the epigenome, whose alterations may underlie several phenomena related to chronic adult-onset disease that are not explained by genetics alone. The stepwise process of carcinogenesis can be accelerated or halted for various reasons, including inherited susceptibility and diet. The human multi-organ cancer syndromes hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) as well as their murine counterparts, the Mlh1+/- mouse and the ApcMin/+ mouse, will be used as shortcuts to study the interplay between the epigenome and genome in tumorigenesis and to identify biomarkers of cancer susceptibility, malignant transformation, and tumor progression. This will be achieved by molecular profiling of normal and tumor tissues, cell line studies, in vitro functional assays, and in silico approaches. Additionally, the role that the epigenome plays to mediate the effects of the Western type diet on colorectal tumorigenesis will be examined in the mouse. Unlike genetic changes, epigenetic alterations are potentially reversible, which makes them promising targets for preventive and therapeutic interventions.