Fig. 1

Evolutional pathways for colorectal morphogenesis. The traditional pathway is the most homogenous pathway, originating from tubular adenoma (via adenomatous polyposis coli (APC) and subsequently Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation) and leading to adenocarcinoma [via tumor protein 53 (TP53) mutation]. This pathway is characterized by chromosomal instability (CIN), negative CpG island methylator phenotype (CIMP), and average outcome. The serrated pathway is also the most homogenous pathway, originating from sessile serrated adenoma/polyps (SSA/P) via B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation and CIMP-high (CIMP-H) and leading to adenocarcinoma via MutL homolog 1 (MLH1) promoter methylation and microsatellite instability-high (MSI-H). This pathway is characterized by good prognosis. The alternative pathway is more heterogeneous and may arise mostly from villous adenoma and perhaps also from SSA/P and traditional serrated adenoma (TSA) via CIMP-low (CIMP-L) and predominant KRAS but occasional BRAF mutations. This pathway lacks CIN and has the worse prognosis with low responsiveness to chemotherapy. The de novo cancers usually lack KRAS mutation but are significantly associated with TP53 and APC mutations and also loss of heterozygosity (LOH) at chromosome 3p (chr 3p). EMT epithelial-mesenchymal transition, TGF-β transforming growth factor-β, MSI-L MSI-low. A part of this figure was reproduced from figure 1 in Patholog Res Int 2012;2012:509348 authored by Pancione et al. [42], with permission