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

doi:10.1016/j.mrfmmm.2013.04.002

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis

Volumes 745–746, May–June 2013, Pages 6-15

https://doi.org/10.1016/j.mrfmmm.2013.04.002 Get rights and content

Highlights

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We found association of polymorphisms of BER genes with risk of colorectal cancer.
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Patients with CRC: higher sensitivity to DNA damages, reduced efficiency of DNA repair.
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We found association between efficiency of DNA repair and polymorphisms of BER genes.

Abstract

Oxidative damage has been implicated in the pathogenesis of colorectal cancer (CRC). The base excision repair (BER) pathway is the major DNA repair pathway for oxidative DNA damage and genetic variation associated with impaired BER might thus increase a risk of CRC. In this work, we evaluated associations between the repair efficiency of oxidative DNA lesions and single-nucleotide polymorphisms of BER genes: the 194Trp/Arg and the 399Arg/Gln XRCC1, the 326Ser/Cys OGG1 and the 324Gln/His MUTYH and CRC occurrence in a Polish population. These polymorphisms were genotyped in 182 CRC patients and 245 control subjects, using a PCR-RFLP approach. The level of oxidative damage and DNA repair capacity in lymphocytes and CRC tissue samples was evaluated by comet assay using FPG and Nth glycosidases. The 326Ser/Cys OGG1 and the 324Gln/His as well as the 324His/His MUTYH genotypes were found to be associated with an increased CRC risk, while no association was found for the XRCC1 gene polymorphisms. It was also demonstrated the reduced capacity of oxidative damage repair in CRC patients in comparison to healthy controls. Moreover, the decrease efficiency of DNA repair were correlated with the 399Gln/Gln XRCC1 and the 324His/His MUTYH genotypes occurrence in CRC patients. The results obtained in our study indicated an association of OGG1 and MUTYH genes polymorphisms involved in oxidative DNA lesions repair with the risk occurrence of colorectal cancer in Polish patients. It was also found that studied polymorphisms might affect DNA repair capacity suggesting their role in CRC pathogenesis. Finally, we conclude that BER pathway may be an important target for the diagnosis and treatment of colorectal patients.

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, p_corr = 0.096) and the occurrence of the Gln allele (OR 1.672 95% CI: 1.378–2.021, p = 0.021, p_corr = 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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^☆: 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.

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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☆

Highlights

Abstract

Introduction

Section snippets

Patients

Results

Discussion

Conflict of interest statement

Cancer Lett.

Mutat. Res.

Int. J. Hyg. Environ. Health

Cancer Lett.

Cancer Epidemiol.

Eur. J. Cancer

Cancer Lett.

Cancer Lett.

Curr. Opin. Genet. Dev.

Am. J. Hum. Genet.

Food Chem. Toxicol.

Free Radic. Biol. Med.

FEBS Lett.

Risk prediction models for colorectal cancer: a review

Cancer Epidemiol. Biomarkers Prev.

An association between the XRCC1 gene polymorphisms and a family history of gastric cancer

Pol. Gastroenterol.

Association of the hOGG1 Ser326Cys polymorphism with lung cancer risk

Cancer Epidemiol. Biomarkers Prev.

Association of MUTYH Gln324His and APEX1 Asp148Glu with colorectal cancer and smoking in a Japanese population

J. Exp. Clin. Cancer Res.

G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences

Behav. Res. Methods

No association between the Arg194Trp and Arg399Gln polymorphisms of the XRCC1 gene and colorectal cancer risk and progression in a Polish population

Exp. Oncol.

Polymorphisms of the DNA repair genes XRCC1 and XRCC3 and risk of lung and colorectal cancer: a case–control study in a Southern Italian population

Anticancer Res.

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Asian Pac. J. Cancer Prev.

XRCC1 Arg399Gln and Arg194Trp polymorphisms in prostate cancer risk: a meta-analysis

Prostate Cancer Prostatic Dis.

Polymorphisms in DNA repair genes XRCC1, XRCC3 and XPD, and colorectal cancer risk: a case–control study in an Indian population

J. Cancer Res. Clin. Oncol.