SMAD4 and colorectal carcinoma: While APC, TP53, and SMAD4 mutations play a significant role in CRC progression [448], it is important to understand that cancer is a multifactorial disease, and other genetic alterations or molecular mechanisms are also involved in evading growth suppressors through the override of cell cycle restriction points [449], enhancing DNA damage tolerance (DDT) mechanisms [450], and bypassing senescence to render immortality [451,452].