Molecular mechanisms in colitis-associated colorectal cancer

Abstract

Sustained chronic inflammation of the large intestine leads to tissue damage and repair, which is associated with an increased incidence of colitis-associated colorectal cancer (CAC). The genetic makeup of CAC is somewhat similar to sporadic colorectal carcinoma (sCRC), but there are differences in the sequence and timing of alterations in the carcinogenesis process. Several models have been developed to explain the development of CAC, particularly the "field cancerization" model, which proposes that chronic inflammation accelerates mutagenesis and selects for the clonal expansion of phenotypically normal, pro-tumorigenic cells. In contrast, the "Big Bang" model posits that tumorigenic clones with multiple driver gene mutations emerge spontaneously. The details of CAC tumorigenesis-and how they differ from sCRC-are not yet fully understood. In this Review, we discuss recent genetic, epigenetic, and environmental findings related to CAC pathogenesis in the past five years, with a focus on unbiased, high-resolution genetic profiling of non-dysplastic field cancerization in the context of inflammatory bowel disease (IBD).

Fig. 1. Top recurrent mutations between nondysplastic UC and CAC.

Frequency of driver mutations in clones from ulcerative colitis nondysplastic colon, colitis-associated carcinoma (CAC), and sporadic colorectal carcinoma (sCRC) in top IL-17-NF-kB pathway genes and bottom frequently mutated established cancer drivers. Non-dysplastic UC most recurrently enriches for IL-17-NF-kB signaling pathway mutations, in addition to more well-recognized cancer drivers such as ARID1A, FBXW7, and KRAS. Intriguingly, these pathway mutations are virtually absent in CAC tumors, as well as sCRC. Conversely, the most recurrently mutated genes in CAC tumors are poorly represented in non-dysplastic UC except KRAS. Figure reproduced from Kakiuchi et al., 2019, with permission from Springer Nature. For more details, please refer to the original study.

Fig. 2. Aneuploidy is an early finding in colitis-associated dysplasia.

A visualization of genome-wide copy number alterations in normal IBD colon, low-grade dysplasia IBD colon (LGD), mixed-grade IBD colon (LGD/HGD), high-grade dysplasia IBD colon (HGD), and colitis-associated carcinoma (CAC). Sporadic CRC tumors used for comparison are microsatellite stable. Blue or red bars indicate statistically significant arm losses or gains, respectively. Figure reproduced from Baker et al., 2019, reproduced under an open-access Creative Commons CC By 4.0 license. For more details, please refer to the original study.

Fig. 3. Overview of genomic alterations and their sequence in CAC.

In contrast to the classic Vogelgram model of sCRC progression, p53 loss is an early event in CAC rather than late. APC mutations on the other hand, are observed to occur after p53 loss rather than before, as classically observed in sCRC. Copy number alteration and aneuploidy are substantial in both CAC and sCRC, with similar regions experiencing gains and losses in both. Figure reproduced from Baker et al., 2019, reproduced under an open-access Creative Commons CC By 4.0 license. For more details, please refer to the original study.

Fig. 4. Single nucleotide alteration phylogenic analysis of CAC.

Phylogenetic trees constructed from eight independent ulcerative colitis (UC) or Crohn disease patients (CD). Driver mutations, annotated, appear early and simultaneously in phylogenetic history. Top, 8 cases showing simultaneous truncal emergence of multiple mutations in a single clone. Bottom, 1 case showing sequential truncal emergence of multiple mutations accumulating over genetically distinct clones (UC06, boxed in orange). Figure reproduced from Baker et al., 2019, reproduced under an open-access Creative Commons CC By 4.0 license. For more details, please refer to the original study.

Fig. 5. The consensus molecular subtypes of CAC.

Bulk tumor RNA-seq of independent microsatellite stable sporadic CRC (MSS sCRC) and microsatellite stable colitis-associated CRC (MSS IBD-CRC) tumors were binned into the consensus molecular subtypes of CRC. This initial study suggests CAC may most transcriptionally aligned with the CMS4 subtype, characterized by stromal, CD4 + T cell, and monocyte involvement. Figure from Rajamaki et al., 2021, reproduced under an open-access Creative Commons BY-NC-ND 4.0 license. For more details, please refer to the original study.

Fig. 6. Genotoxic metabolites produced by the gut microbiome in IBD.

Several Clostridium and E. coli species, as well as the recently characterized M. morganii produce novel genotoxic metabolites that appear more potent than those from colibactin producing E. coli. Mean fluorescent intensity (MFI) of the double-stranded DNA break marker γH2AX in HeLa cells treated with metabolite extracts from indicated bacterial strains, including the genotoxin colibactin (clb) producing and non-producing strains of E. coli. Figure from Cao et al., 2022, reproduced with permission from Science. For more details, please refer to the original study.