Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
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☆
Introduction
Among malicious tumors, CRC is the second most common. The risk of developing CRC significantly increases with age and reaches its peak in the seventh decade of life. Early diagnosis is one of the most important therapy factors and significantly improves the chances of patients survival. The causes of CRC have not yet been established. It is estimated that in 15–35% of cases the cancer is familial, the rest are sporadic and among them approximately 3% are caused by mutations of strongly predisposed genes [1]. Despite the cause of most CRCs being environmental factors, studies show that individual predispositions for developing this cancer may depend on genetic changes, including changes in genes involved in the process of DNA repair. It is estimated that the daily number of DNA damage in human cell ranges from 100 to 500 spontaneous deamination and 20,000–40,000 single-stranded breaks [2]. The main source of DNA damage is oxidative damage arising as a result of oxidative stress – imbalance between the intensity of oxidative processes that induce the formation of reactive oxygen species (ROS) and antioxidant systems of counteracting them. In addition to damage caused by the activity of endogenous ROS generated in normal metabolic processes of cells, especially in the process of oxidative deamination DNA is exposed to damage by exogenous factors such as: ionizing radiation, high temperature or chemical mutagens [3]. All of these types of damage, if not repaired, may underlie the process of carcinogenesis. In mammalian cells there are four basic mechanisms of DNA repair: base-excision repair (BER), nucleotide-excision repair (NER), mismatch repair (MMR) and double-strand breaks repair (DSB). Damage to DNA bases, caused by deamination, oxidation or alkylation, is repaired mainly by base-excision. Among the known polymorphisms of the DNA repair genes, the polymorphisms of XRCC1, OGG1 and MUTYH genes have been repeatedly studied as potentially connected with susceptibility to the occurrence of various cancers. Because the polymorphisms of these genes may affect the level of DNA repair, leading to carcinogenesis, it is important to establish the molecular causes of the carcinogenetic process [2], [3]. Genetic tests enable the diagnosis of individuals with increased risk of developing cancer and helps to put them into a group which can be placed under observation and treated with prophylactics.
Section snippets
Patients
Our hospital-based investigation comprised a series of 182 sporadic CRC patients and 200 non-affected control subjects. Cases included unrelated men and women, each with a histologically confirmed diagnosis of CRC. This group included 107 men and 75 women (average age 63 years ± 8 years), who underwent surgery in the Department of General and Colorectal Surgery at the Medical University of Lodz between 2009 and 2011. The main familial syndrome like FAP and Lynch Syndrome were excluded from the
Results
Table 2 displays the distribution of genotypes and frequencies allele of XRCC1, OGG1 and MUTYH polymorphisms. All ORs were adjusted for age and sex. The distribution of genotypes in control group was consistent with Hardy–Weinberg equilibrium for all studied polymorphisms. The results showed that the 399Gln/Gln genotype of XRCC1 gene (OR 2.034 95% CI: 1.230–3.967, p = 0.032, pcorr = 0.096) and the occurrence of the Gln allele (OR 1.672 95% CI: 1.378–2.021, p = 0.021, pcorr = 0.063) as well as (OR 1.825
Discussion
CRC is one of the most common tumor and early diagnosis is critical for patients survival. Recent studies have reported that individual risk for CRC might depend on genetic factors, including DNA repair. In this study we analyzed the distribution of polymorphisms of XRCC1, OGG1 and MUTYH genes in patients with CRC according to healthy subjects in the Polish population. The 399Arg/Gln XRCC1 gene polymorphism demonstrated correlation between the occurrence of genotype the Gln/Gln and the 399Gln
Conflict of interest statement
The authors declare that they have no conflict of interest.
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2020, Experimental and Molecular PathologyCitation Excerpt :Nevertheless, XRCC1 A399G heterozygous cases showed no relation with CRC risk (Forat-Yazdi et al., 2015; Huang et al., 2015). Other studies, however, showed no relationship between XRCC1 Arg399Gln polymorphism and susceptibility for CRC or polyp development (Przybylowska et al., 2013; Gsur et al., 2011). Other XRCC gene polymorphisms have been examined for their association with risk of CRC.
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This work was supported by grant no. N402 422138 from Polish Ministry of Science and Higher Education and by grants of UM in Lodz 502-17-555 and 502-54-012.