Efficiency of Base Excision Repair of Oxidative DNA Damage and Its Impact on the Risk of Colorectal Cancer in the Polish Population

DNA oxidative lesions are widely considered as a potential risk factor for colorectal cancer development. The aim of this work was to determine the role of the efficiency of base excision repair, both in lymphocytes and in epithelial tissue, in patients with CRC and healthy subjects. SNPs were identified within genes responsible for steps following glycosylase action in BER, and patients and healthy subjects were genotyped. A radioisotopic BER assay was used for assessing repair efficiency and TaqMan for genotyping. Decreased BER activity was observed in lymphocyte extract from CRC patients and in cancer tissue extract, compared to healthy subjects. In addition, polymorphisms ofEXO1,LIG3, andPolBmay modulate the risk of colorectal cancer by decreasing (PolB) or increasing (LIG3andEXO1) the chance of malignant transformation.

Download Full-text

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

International Journal of Molecular Sciences ◽

10.3390/ijms21072473 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2473 ◽

Cited By ~ 4

Author(s):

Pavel Vodicka ◽

Marketa Urbanova ◽

Pavol Makovicky ◽

Kristyna Tomasova ◽

Michal Kroupa ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Damage ◽

Dna Repair ◽

Base Excision Repair ◽

Oxidative Dna Damage ◽

Excision Repair ◽

Sporadic Colorectal Cancer ◽

Base Excision ◽

Colorectal Cancer Patients

Oxidative stress with subsequent premutagenic oxidative DNA damage has been implicated in colorectal carcinogenesis. The repair of oxidative DNA damage is initiated by lesion-specific DNA glycosylases (hOGG1, NTH1, MUTYH). The direct evidence of the role of oxidative DNA damage and its repair is proven by hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome), where germline mutations cause loss-of-function in glycosylases of base excision repair, thus enabling the accumulation of oxidative DNA damage and leading to the adenoma-colorectal cancer transition. Unrepaired oxidative DNA damage often results in G:C>T:A mutations in tumor suppressor genes and proto-oncogenes and widespread occurrence of chromosomal copy-neutral loss of heterozygosity. However, the situation is more complicated in complex and heterogeneous disease, such as sporadic colorectal cancer. Here we summarized our current knowledge of the role of oxidative DNA damage and its repair on the onset, prognosis and treatment of sporadic colorectal cancer. Molecular and histological tumor heterogeneity was considered. Our study has also suggested an additional important source of oxidative DNA damage due to intestinal dysbiosis. The roles of base excision repair glycosylases (hOGG1, MUTYH) in tumor and adjacent mucosa tissues of colorectal cancer patients, particularly in the interplay with other factors (especially microenvironment), deserve further attention. Base excision repair characteristics determined in colorectal cancer tissues reflect, rather, a disease prognosis. Finally, we discuss the role of DNA repair in the treatment of colon cancer, since acquired or inherited defects in DNA repair pathways can be effectively used in therapy.

Download Full-text