SMAD4 and adenoma: This is best illustrated by the adenoma to adenocarcinoma sequence: mutations in the APC/β-catenin/TCF4 pathway induce the formation of low grade benign tumors (adenomas) that upon the acquisition of further mutations (k-Ras, SMAD-4, p53 and others) increase in grade and then become malignant (adenocarcinomas) [79,81].