Colorectal carcinogenesis: Road maps to cancer

Abstract

This review explores the chief genetic and epigenetic events that promote pathological progression in colorectal carcinogenesis. This article discusses the molecular and pathological basis for classifying colorectal neoplasia into suppressor, mutator and methylator pathways. These differing mechanisms of genomic instability are associated with specific cancer characteristics, and may provide the opportunity for more effective prevention and surveillance strategies in the future. This is the first review in a series of five topics outlining important and developing aspects of colorectal cancer. This article reviews recent developments in defining colorectal cancer pathways. In particular, we identify the chief genetic events that advance neoplasia, outline the histopathological correlates of these molecular perturbations and, where possible, contrast these differing mechanisms to emphasize the clinical value of dissecting out these road maps to cancer. CaNCeR: a DIsTURbaNCe Of mUTaTION, RepaIR aND expRessIONColorectal carcinogenesis requires a previously normal cell to accumulate multiple genetic alterations and establish successive clones, each characterized by relative growth advantage. This growth advantage may be conferred through an increased rate of proliferation, impaired apoptosis, or both. Most cancers probably require between 6 to 10 clonal events to reach their final malignant phenotype, which also requires the acquisition of metastatic traits [10] . In addition to simple growth advantage, the "successful" pre-cancerous clone must develop a cellular environment permissive of future mutation [7] . This process, referred to as genomic instability, ensures that subsequent strategic mutations occur at increasingly greater likelihood. Genomic instability is critical in carcinogenesis. It accelerates the neoplastic evolutionary process, by increasing the mutation rate induced by the background mutagenic challenge. Without genomic instability, the acquisition of new mutations would occur far too slowly for a cancer to develop during a person's lifetime [11] . Genomic integrity in a nor mal cell is under careful scrutiny. The cell cycle and mitotic spindle checkpoints are critical in this process to ensure that cell proliferation only follows correct replication and organization of genetic material, respectively. If the genetic damage is too great for repair, the cell avoids propagating the damaged DNA by undergoing apoptosis. When one particular type of genomic instability predominates and neoplasias progress through characteristic histopathological stages with similar genetic alterations, then it is appropriate to consider such a process as a discrete pathway.There are two chief categories of genomic instability in colorectal cancer. The most common is chromosomal instability (CIN), in which the requisite genetic events occur through the accumulation of numerical or structural chromosomal abnormalities (aneuploidy) [10] . The other main type of genomic instability is microsatellite instabilit...

K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas

“…They may constitute a dipole; whichever member of the pair is destined to occur first, it activates inevitably the second pole, which acts complementary to the initial event and is a prerequisite for the complete action of the dipole to fulfill (Figures 3, 4). The fact that K-ras mutation may precede APC inactivation agrees with recent reviews that have placed K-ras as the initiating event of the process (14,91).…”

Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers

“…The development of colorectal cancer results from the sequential accumulation of mutations or deletions in the coding sequence of a number of tumor suppressor genes and oncogenes, together with aberrant activity of molecules controlling genomic stability. COX-2, p53, epidermal growth factor receptor (EGFR), b-catenin/adenomatous polyposis coli (APC), K-ras and so on, all may play important roles in colorectal carcinogenesis (Worthley et al, 2007). For example, more than 80% of colorectal cancer have either b-catenin or APC mutation, leading to the activation of this pathway, although EGFR is overexpressed in more than 50% of colorectal adenocarcinomas and is associated with a more aggressive and invasive phenotype.…”

Pharmacogenetics and biomarkers in colorectal cancer

“…5,17,18 Normally, methylation of cytosine-guanosine dinucleotides (CpG) occurs throughout DNA genome, whereas gene promoters contain mainly unmethylated CpG islands, events that are reversed in carcinogenesis (that is, global genomic hypomethylation with promoter CpG islands hypermethylation). 18 There are numerous published preclinical studies suggesting a strong association of CpG islands methylation phenotype with BRAF mutations and also to a lesser degree with MSI.…”