Studies of cancers of the digestive system have identified specific perturbations of the ISG15 pathway, including the dysregulation of ISG15 expression, sequence variation of ISG15 pathway genes, and ISGylation [107, 135, 136], including elevated ISG15 expression in tumors of the esophagus [139], stomach [63], colon/rectum [140], liver [136], and pancreas [141]. Here, ISG15 is linked to digestive system cancer.