It has been widely accepted that mutations in three major gene clusters, APC, KRAS, and TP53, are sufficient to initiate CRC (21, 22), while BRAF, PIK3CA, and SMAD4, which are also listed as the most frequently mutated genes in CRC (23), are identified as important drivers to promote the progression (24). This evidence concerns the gene SMAD4 and colorectal carcinoma.