The Cellular Response to Oxidatively Induced DNA Damage and Polymorphism of Some DNA Repair Genes Associated with Clinicopathological Features of Bladder Cancer

Abstract

Genome instability and impaired DNA repair are hallmarks of carcinogenesis. The study was aimed at evaluating the DNA damage response in H2O2-treated lymphocytes using the alkaline comet assay in bladder cancer (BC) patients as compared to clinically healthy controls, elderly persons, and individuals with chronic inflammations. Polymorphism in DNA repair genes involved in nucleotide excision repair (NER) and base excision repair (BER) was studied using the PCR-RFLP method in the Belarusian population to elucidate the possible association of their variations with both bladder cancer risk and clinicopathological features of tumors. The increased level of H2O2-induced DNA damage and a higher proportion of individuals sensitive to oxidative stress were found among BC patients as compared to other groups under study. Heterozygosity in the XPD gene (codon 751) increased cancer risk: OR (95% CI) = 1.36 (1.03–1.81), p = 0.031. The frequency of the XPD 312Asn allele was significantly higher in T ≥ 2 high grade than in T ≥ 2 low grade tumors (p = 0.036); the ERCC6 1097Val/Val genotype was strongly associated with muscle-invasive tumors. Combinations of homozygous wild type alleles occurred with the increased frequency in patients with non-muscle-invasive tumors suggesting that the maintenance of normal DNA repair activity may prevent cancer progression.

Polymorphisms of DNA repair genes are associated with colorectal cancer in patients with Lynch syndrome

“…MUTYH has a functional role of repairing 8-hydroxyguanine mismatches that occur as a result of adenine glycosylase activity (Slupska, Luther, Chiang, Yang, & Miller, 1999). A previous study indicated that the homozygous CC genotype of rs3219489 was associated with an increased risk of CRC when compared to the GG genotype (Picelli et al, 2010).…”

“…However, DNA repair genes are polymorphic, and the single nucleotide polymorphism (SNP) of these genes is associated with cancer development (Moreno et al., ). Polymorphisms of MLH1 , APEX1 , MUTYH , OGG1 , NUDT1 , and XRCC5 are associated with sporadic CRC (Kim et al., ; Lai et al., ; Yang et al., ) and other site‐specific cancers (Li et al., ; Savina et al., ; Smith et al., ). However, recent studies have indicated that XPA and ERCC2 SNPs are not associated with sporadic CRC (Chang et al., ; He, Deng, & Luo, ).…”

Comet assay: an essential tool in toxicological research

“…An interpretation in terms of cancer susceptibility seems not to be reasonable (Collins and Azqueta 2012). Nevertheless, accumulation of oxidatively induced DNA damage might serve as a potential biomarker of genome instability predisposing to cancer as recently shown by comparing the damage response in H 2 O 2 -treated lymphocytes using the comet assay in bladder cancer patients as compared to healthy controls, elderly persons, and individuals with inflammations (Savina et al 2016).…”

“…Some excision repair gene polymorphisms modify the susceptibility to bladder cancer. For example, polymorphisms (codons 312 and 751) in xeroderma pigmentosum group D (XPD) gene increase cancer risk, whereas a combination of homozygous wild-type genotypes were associated with a twice lower frequency in T ≥ 2 carcinomas suggesting that the maintenance of normal DNA repair activity seems to inhibit cancer initiation and/or cancer progression (Savina et al 2016). …”

Interplay of host genome and tumour genome in bladder cancer

“…Нами ранее было показано, что некоторые полиморфизмы генов эксцизионной репарации оснований (OGG1 rs1052133 и XRCC1 rs25487) и нуклеотидов (ERRC2/XPD rs1799793 и ERRC6/CSB rs2228526) модифицируют предрасположенность к раку мочевого пузыря [2], а также ассоциированы с клинико-патологическими характеристиками заболевания [3][4][5]. Кроме того, установлено, что дикие аллели генов ERCC2/XPD (rs1799793, rs13181) и ERCC6/CSB (rs2228526, rs2228528) благоприятствуют долгожительству, уменьшают риск развития РМП (особенно после 80 лет) у их носителей, а также ассоциированы с низкой степе-нью распространенности и злокачественности опухоли, редким рецидивированием [6].…”