Figure 4.

Progression of colorectal tumors with CIN. The hallmark of the CIN pathway is aneuploidy. Initiation of neoplasia in this pathway occurs with interruption of components of the Wnt signaling pathway, including somatic mutation in one allele and loss of heterozygosity of the second normal allele of the APC gene, and is seen in dysplastic ACF histologically. Progression is then driven by successive waves of cellular clonal expansion that acquire enhanced growth characteristics and include mutational activation of the proto-oncogene KRAS and mutation of TP53 with subsequent loss of heterozygosity of the normal remaining TP53 allele to allow carcinoma formation. In some colorectal tumors, mutational activation of PIK3CA occurs late in the adenoma-carcinoma sequence. Several TGF-β signaling molecules are also affected in CIN progression, including mutations of the kinase domain of TGFBR2 and loss of heterozygosity at chromosome 18q, the site of SMAD4 and SMAD2. Several genes are believed to be involved in metastasis and include gene amplification of PRL3.