CIN tumours usually arise as a consequence of a combination of oncogene activation (e.g. KRAS, PIK3CA) and tumour suppressor gene inactivation (e.g. APC, SMAD4 and TP53) by allelic loss and mutation, which go along with changes in tumour characteristics in the adenoma to carcinoma sequence, as first described by Fearon and Vogelstein in 1990 [10]. Here, SMAD4 is linked to neoplasm.