SMAD4 and adenoma: Miyaki et al (1999) reported that they found no Smad4 mutation in adenomas and intramucosal carcinomas, although the frequency of the mutation increased as the invasiveness of the tumour grew. Furthermore, they found a higher frequency of mutation in colorectal cancers with distant metastasis compared to those without distant metastasis. Their study strongly indicated that the Smad4 gene correlates with malignancy in the advanced stage and is the target gene on 18q21.1, the locus indicative of tumour progression and poorer prognosis when deleted.