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.
An association selected polymorphisms of XRCC1, OGG1 and MUTYH gene and the level of efficiency oxidative DNA damage repair with a risk of colorectal cancer.Mutat Res. 2013 May-Jun;745-746:6-15. doi: 10.1016/j.mrfmmm.2013.04.002. Epub 2013 Apr 23. Mutat Res. 2013. PMID: 23618615
Slow accumulation of mutations in Xpc-/- mice upon induction of oxidative stress.DNA Repair (Amst). 2013 Dec;12(12):1081-6. doi: 10.1016/j.dnarep.2013.08.019. Epub 2013 Sep 29. DNA Repair (Amst). 2013. PMID: 24084170 Free PMC article.
Origin of Somatic Mutations in β-Catenin versus Adenomatous Polyposis Coli in Colon Cancer: Random Mutagenesis in Animal Models versus Nonrandom Mutagenesis in Humans.Chem Res Toxicol. 2017 Jul 17;30(7):1369-1375. doi: 10.1021/acs.chemrestox.7b00092. Epub 2017 Jun 15. Chem Res Toxicol. 2017. PMID: 28578586 Review.
AP endonuclease 1 prevents the extension of a T/G mismatch by DNA polymerase β to prevent mutations in CpGs during base excision repair.DNA Repair (Amst). 2016 Jul;43:89-97. doi: 10.1016/j.dnarep.2016.03.006. Epub 2016 Mar 22. DNA Repair (Amst). 2016. PMID: 27183823 Free PMC article.
Mismatch Repair and Colon Cancer: Mechanisms and Therapies Explored.Trends Mol Med. 2016 Apr;22(4):274-289. doi: 10.1016/j.molmed.2016.02.003. Epub 2016 Mar 9. Trends Mol Med. 2016. PMID: 26970951 Review.