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, 12, 111-132

How Does Inflammation Drive Mutagenesis in Colorectal Cancer?

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How Does Inflammation Drive Mutagenesis in Colorectal Cancer?

Chia Wei Hsu et al. Trends Cancer Res.

Abstract

Colorectal cancer (CRC) is a major health challenge worldwide. Factors thought to be important in CRC etiology include diet, microbiome, exercise, obesity, a history of colon inflammation and family history. Interventions, including the use of non-steroidal anti-Inflammatory drugs (NSAIDs) and anti-inflammatory agents, have been shown to decrease incidence in some settings. However, our current understanding of the mechanistic details that drive CRC are insufficient to sort out the complex and interacting factors responsible for cancer-initiating events. It has been known for some time that the development of CRC involves mutations in key genes such as p53 and APC, and the sequence in which these mutations occur can determine tumor presentation. Observed recurrent mutations are dominated by C to T transitions at CpG sites, implicating the deamination of 5-methylcytosine (5mC) as a key initiating event in cancer-driving mutations. While it has been widely assumed that inflammation-mediated oxidation drives mutations in CRC, oxidative damage to DNA induces primarily G to T transversions, not C to T transitions. In this review, we discuss this unresolved conundrum, and specifically, we elucidate how the known nucleotide excision repair (NER) and base excision repair (BER) pathways, which are partially redundant and potentially competing, might provide a critical link between oxidative DNA damage and C to T mutations. Studies using recently developed next-generation DNA sequencing technologies have revealed the genetic heterogeneity in human tissues including tumors, as well as the presence of DNA damage. The capacity to follow DNA damage, repair and mutagenesis in human tissues using these emerging technologies could provide a mechanistic basis for understanding the role of oxidative damage in CRC tumor initiation. The application of these technologies could identify mechanism-based biomarkers useful in earlier diagnosis and aid in the development of cancer prevention strategies.

Keywords: DNA repair; base excision repair; colorectal cancer; deamination; inflammation; mutations; oxidation.

Conflict of interest statement

CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Multiple pathways for the formation of colorectal tumors. This abbreviated scheme shows the suspected sequence for mutations of the APC and p53 genes in colitis-associated and sporadic colorectal cancer.
Fig. 2
Fig. 2
Mutational hotspots observed in the APC (upper) [–31] and p53 (lower) [–42] genes frequently mutated in human colorectal tumors. The DNA coding sequence for each protein is shown above a three-dimensional rendering of the protein (PDB ID:1TSR).
Fig. 3
Fig. 3
Observed single-base mutations reported for CRC. Orange bars represent types of TP53 mutations in all tumors [52], grey bars represent types of TP53 mutations in CRC [52], and blue represents substitution mutations in all genes in CRC reported in the COSMIC database v81 [54].
Fig. 4
Fig. 4
The hydrolytic deamination of cytosine and 5-methylcytosine.
Fig. 5
Fig. 5
Pathway for generating a C to T transition mutation in a human tumor.
Fig. 6
Fig. 6
Transition mutations generated from the deamination of 5mC versus transversion mutations generated by oxidation and miscoding of guanine.
Fig. 7
Fig. 7
Competition between short-patch BER repair pathways. In the above example, the T of a T:8oxoG mispair can be removed by TDG or MBD4 and replaced by C (upper pathway) or the 8oxoG can be removed by hOGG1 and replaced by A (lower pathway).
Fig. 8
Fig. 8
The conversion of a T:G mispair to a T:A mutation by guanine oxidation followed by long-patch base excision repair. Long-patch BER could convert the T:G mispair to a T:A mutation; however, this pathway is blocked by the APC protein.
Fig. 9
Fig. 9
Colorectal cancer incidence increases with age. Colorectal cancer occurs more frequently in patients with a history of colitis (red line) than in patients with sporadic CRC (green line) [173]. Recent developments in treating the underlying inflammation in patients with colitis have reduced CRC incidence to that of patients without colitis (A). Further developments in monitoring inflammation and DNA damage history could reduce CRC incidence (blue line, B). Somatic mutations in tissues of patients diagnosed with colorectal cancer increase with age (dotted line, trend line from Tomasetti et al.) [171]. Measurement of mutations (synonymous and passenger) might provide a history of DNA damage in a given tissue or alternative source of cell-free DNA.

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