Genetic and epigenetic events generate multiple pathways in colorectal cancer progression

Abstract

Colorectal cancer (CRC) is one of the most common causes of death, despite decades of research. Initially considered as a disease due to genetic mutations, it is now viewed as a complex malignancy because of the involvement of epigenetic abnormalities. A functional equivalence between genetic and epigenetic mechanisms has been suggested in CRC initiation and progression. A hallmark of CRC is its pathogenetic heterogeneity attained through at least three distinct pathways: a traditional (adenoma-carcinoma sequence), an alternative, and more recently the so-called serrated pathway. While the alternative pathway is more heterogeneous and less characterized, the traditional and serrated pathways appear to be more homogeneous and clearly distinct. One unsolved question in colon cancer biology concerns the cells of origin and from which crypt compartment the different pathways originate. Based on molecular and pathological evidences, we propose that the traditional and serrated pathways originate from different crypt compartments explaining their genetic/epigenetic and clinicopathological differences. In this paper, we will discuss the current knowledge of CRC pathogenesis and, specifically, summarize the role of genetic/epigenetic changes in the origin and progression of the multiple CRC pathways. Elucidation of the link between the molecular and clinico-pathological aspects of CRC would improve our understanding of its etiology and impact both prevention and treatment.

Figure 1

Genomic instability and multiple pathways in colorectal cancer pathogenesis. (a) Comparison of the numerical chromosomal abnormalities between two representative colon cancer cell lines characterized by CIN (highly rearranged aneuploid karyotype) and MSI (diploid karyotype), respectively. The images are publicly available on the web at: http://www.path.cam.ac.uk. (b) Three distinct parallel pathways with the approximate indicated prevalence are implicated in colon cancer pathogenesis: traditional, alternative, and serrated. The sequential of genetic and epigenetic changes occurring in each pathway are simplified, along with the characteristic precursor lesions (adenomas) and distinctive molecular features of the corresponding carcinomas. The traditional and serrated pathways are more homogeneous and clearly distinguishable; the alternative is more heterogeneous. The best known genetic/epigenetic alterations are indicated in bold, the poorly understood or hypothetical pathways are indicated in italics. APC, adenomatous polyposis coli; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; CIMPL, CIMP-low; CIN, chromosomal instability; MSS, microsatellite stable; BER, base excision repair pathway; Methyl, DNA methylation silencing in yet unknown genes; WNT, wingless pathway; EMT, epithelial mesenchymal transition; TGFβ, transforming growth factor-beta; LOH, loss-of-heterozigosity. Note: tumor microenvironment indicates the crosstalk between cancer cells and cells of the neoplastic stroma.

Figure 2

Epigenetic alterations may differentiate the traditional and serrated pathway at early stage of tumor development. (a) The serrated and traditional pathways show clinical differences, especially when referred to the site of origin of the tumor. The serrated pathway tends to be localized to the proximal (right) colon; the traditional to the distal (left) colon. The main molecular alterations that clearly distinguish the two pathways are the presence (+)/absence (−) of the CIMP phenotype and different genetic characteristics (BRAF/MSI versus APC/CIN). (b) The colonic epithelium consists of spatially separated, nonproliferative/differentiated cells at the tip of the villi, marked by cytokeratin 20 and proliferative/undifferentiated cell populations marked by Ki67. The molecular mechanisms underlying CIMP and CIN are still unknown; however, these alterations may evolve in a nonrandom fashion. According to the top-down model [31], the traditional pathway may arise from genetic lesions (APC mutations) confined to the upper crypt compartment. In contrast, the serrated pathway may originate in the lower crypt compartment by yet uncharacterized genetic and/or epigenetic lesions. Current evidences support the idea that the specific functions played in the lower compartment are maintained by an epigenetic program finely regulated by PRCs [, –35]. Initial lesions in cells of this compartment may predispose to the epigenetic characteristics of the adult cancer through an “epigenetic memory.” This may explain why these specific precursor lesions proliferate downward or laterally, are age-related, rapidly progressive, and prone to CIMP. APC, adenomatous polyposis coli; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; CIN, chromosomal instability; polycomb repressive complexes (PRCs).

Figure 3

CRC classification in molecular subgroups. (a) Five molecular colorectal cancer subgroups have been proposed, stratified on the basis of genomic instability, presence/absence of CIMP [10]. The approximate frequencies of each CRC subtype in the Western population are illustrated. (b) Because the currently used criteria for CIN analysis are not uniform, as compared to MSI and CIMP, a classification into only 4 molecular subtypes has been proposed [77, 78]. The approximate frequencies in the Western population are illustrated. The distribution of the CIMP subgroup appears to correlate with ethnic differences (see text), suggesting that predisposition to the CIMP pathway may be tied to the contribution of yet unknown gene-environment interactions. MSI, microsatellite instability; CIMP, CpG Island methylator phenotype; CIN, chromosomal instability; CIMPL, CIMP Low.