How does inflammation drive mutagenesis in colorectal cancer?

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.