SMAD4 and cancer: The conventional chromosomal instability mechanism is characterized by the accumulation of mutations that are initiated after mutational inactivation in the adenomatous polyposis coli (APC), accompanied by oncogenes activations including ki-ras2 Kirsten rat sarcoma viral oncogene homolog (Kras), cyclooxygenase-2 (COX2) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF), tumor suppressor genes silencing including TP53, Deleted in colon cancer/Deleted in pancreatic cancer locus4 (DCC/DPC4) and loss of heterozygosity of chromosome 18 [171, 172].