Colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, and esophageal cancer are leading causes of cancer related deaths worldwide. A fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological processes of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the clinical behavior of the pre-cancers and cancers and can be used as biomarkers for cancer risk determination, early detection of cancer and pre-cancer, determination of the prognosis of cancer and prediction of the response to therapy.