Genomic instability and colon carcinogenesis: from the perspective of genes

Abstract

Colon cancer is the second most lethal cancer; approximately 600,000 people die of it annually in the world. Colon carcinogenesis generally follows a slow and stepwise process of accumulation of mutations under the influence of environmental and epigenetic factors. To adopt a personalized (tailored) cancer therapy approach and to improve current strategies for prevention, diagnosis, prognosis, and therapy overall, advanced understanding of molecular events associated with colon carcinogenesis is necessary. A contemporary approach that combines genetics, epigenomics, and signaling pathways has revealed many genetic/genomic alterations associated with colon cancer progression and their relationships to a genomic instability phenotype prevalent in colon cancer. In this review, we describe the relationship between gene mutations associated with colon carcinogenesis and a genomic instability phenotype, and we discuss possible clinical applications of genomic instability studies. Colon carcinogenesis is associated with frequent mutations in several pathways that include phosphatidylinositol 3-kinase, adenomatous polyposis coli, p53 (TP53), F-box and WD repeat domain containing 7, transforming growth factor-β, chromosome cohesion, and K-RAS. These genes frequently mutated in pathways affecting colon cancer were designated colon cancer (CAN) genes. Aberrations in major colon CAN genes have a causal relationship to genomic instability. Conversely, genomic instability itself plays a role in colon carcinogenesis in experimental settings, as demonstrated in transgenic mouse models with high genomic instability. Thus, there is a feedback-type relationship between CAN gene mutations and genomic instability. These genetic/genomic studies have led to emerging efforts to apply the knowledge to colon cancer prognosis and to targeted therapy.

Keywords: BubR1; Sgo1; chromosome instability; colon cancer; genomic instability; mice; mitosis.

Figure 1

The “Vogelgram” (modified from the original in Fearon and Vogelstein, 1990). The original “Vogelgram” (Fearon and Vogelstein, 1990) mapped loss of chromosome 5q, 12p, 18q, and 17p, and mutations on APC, K-RAS, DCC, and p53 in a sequential order of cancer progression, although the importance of mutation accumulation, rather than sequential order, was emphasized. DNA hypermethylation also was mapped in the early adenoma stage. Later, gain of Chromosome 20 (Davison et al., ; Wang et al., 2013), gain of chromosome 8q and loss of Chromosome 8p (Bacolod and Barany, 2010), and mutation in DPC4/SMAD4 (Fleming et al., 2013) were added.

Figure 2

How MIN and CIN contribute to genomic instability. Normal cell cycle progression follows G0/G1, S, G2, and M phases (shown in the top with gray-shaded cells). MIN is caused by a defect in DNA repair and/or replication, and is thought to take place mainly during G0/G1, S, or G2 phases in the cell cycle (shown in blue). MIN-type chromosome alteration or its underlying causes also can lead to mitotic errors and CIN (Burrell et al., 2013). CIN is caused by an event in mitosis leading to a chromosome segregation error (e.g., a kinetochore defect, a spindle challenge, a mitotic spindle checkpoint defect, a chromosome cohesion defect; shown in red). CIN also can be caused by an event in a pre-mitotic phase that sets up a mitotic error (e.g., replication stress that can affect mitotic chromosome structure, centrosome mis-regulation that results in multipolar mitosis). CIN-mediated chromosome mis-segregation can lead further to DNA damage, directly caused by cytokinesis machinery or in the process of chromothripsis (Janssen et al., ; Crasta et al., 2012). Failures in cytokinesis and subsequent p53-dependent removal of the cell result in generation of a polyploid cell. Polyploidy can lead to aneuploid offspring cells via multipolar mitosis (Shi and King, 2005). Since p53 is involved in centrosome regulation and clustering in addition to removal of aneuploid/polyploid cells, loss of p53 can permit a polyploid-multipolar mitosis-aneuploid cycle, which would be highly detrimental to genomic integrity.

Figure 3

Defects in major colonic CAN genes are causal to high genomic instability in the colon. Mass-sequencing projects have identified frequently mutated genes and pathways in colon cancer. They are designated as CAN (cancer) genes (Wood et al., ; Chittenden et al., ; Brosens et al., 2010). Colonic CAN genes/pathways include p53, PI3K, APC, FBXW7, TGF-β, and chromosome cohesion. Studies have indicated that each CAN gene mutation can lead to genomic instability either by itself or in concert with other mutations (see text). This effect would explain why nearly all advanced colon cancers show a high degree of genomic instability.