Colitis-associated colon cancer: Is it in your genes?

Abstract

Colitis-associated colorectal cancer (CA-CRC) is the cause of death in 10%-15% of inflammatory bowel disease (IBD) patients. CA-CRC results from the accumulation of mutations in intestinal epithelial cells and progresses through a well-characterized inflammation to dysplasia to carcinoma sequence. Quantitative estimates of overall CA-CRC risks are highly variable ranging from 2% to 40% depending on IBD severity, duration and location, with IBD duration being the most significant risk factor associated with CA-CRC development. Recently, studies have identified IBD patients with similar patterns of colonic inflammation, but that differ with respect to CA-CRC development, suggesting a role for additional non-inflammatory risk factors in CA-CRC development. One suggestion is that select IBD patients carry polymorphisms in various low penetrance disease susceptibility genes, which pre-dispose them to CA-CRC development, although these loci have proven difficult to identify in human genome-wide association studies. Mouse models of CA-CRC have provided a viable alternative for the discovery, validation and study of individual genes in CA-CRC pathology. In this review, we summarize the current CA-CRC literature with a strong focus on genetic pre-disposition and highlight an emerging role for mouse models in the search for CA-CRC risk alleles.

Keywords: Azoxymethane; Colitis-associated colorectal cancer; Dextran sulfate sodium; Forward genetics; Inflammatory bowel disease; Mouse models; Susceptibility genes.

Figure 1

Progression of colitis-associated colorectal cancer. Colitis-associated colorectal cancer progresses through a colitis-dysplasia-carcinoma sequence associated with the development of inflammation, low-grade, high-grade dysplasia and eventually carcinoma due to molecular alterations. IBD: Inflammatory bowel disease; ROS: Reactive oxygen species.

Figure 2

Mouse inflammatory bowel disease and colorectal cancer susceptibility loci. Summary of the current inflammatory bowel disease and colorectal cancer (CRC) loci mapped in inbred mice using forward genetic studies. Arranged by chromosome, each locus has been drawn to scale based on the current mapping data for each. Putative loci or loci that lack mapping data have been excluded. Loci whose precise map location is unknown (indicated with a *) have been drawn centered over the peak marker of association. Ccs: Colon cancer susceptibility; Cdcs: Cytokine deficiency in colitis (Il-10^-/- mouse model of colitis); Dssc: Dextran sulfate sodium-induced colitis; Gpdc: G protein deficient colitis; Hiccs: Helicobacter hepaticus-induced colitis and associated cancer susceptibility; Ibdq: Inflammatory bowel disease quantitative trait loci (Spontaneous SAMP1/YitFC model of colitis); Mom: Modifier of min (Apc^Min+/- model of CRC); Scc: Susceptibility to colon cancer; Tm: Trishuris muris-induced colitis; Tnbs: Trinitrobenzene sulfonic acid susceptibility.