SMAD4 and adenoma: Adenoma-carcinoma sequence. In the carcinogenesis of CRC, several means by which the normal colon cells can become malignant have been described, and studies have centred on the genetic changes which are found in three fundamental categories of genes: 1) tumour suppressor genes or TSG, such as APC, DCC, TP53, SMAD2, SMAD4 and p16INK4a); 2) protooncogenes, such as K-ras, N-ras; 3) DNA repair genes, such as MMR and MUTYH) [43].