Significance of amino acid substitution variants of DNA repair genes in radiosusceptibility of cervical cancer patients; a pilot study
Abstract:
The present pilot study was designed to elucidate the functional significance of amino acid substitution variants of DNA repair genes. Using the peripheral blood lymphocytes (PBLs) from healthy donors and cervical cancer patients, the contribution of four non-synonymous single nucleotide polymorphisms (SNPs) in three base excision repair genes (BER), XRCC1 (Arg194Trp and Arg399Gln), hOGG1 (Ser326Cys), and APE1 (Asp148Glu), to the susceptibility to ionizing radiation were evaluated. The level of initial, oxidative and residual DNA damage produced by 2 Gy was measured by the alkaline single cell gel electrophoresis (the comet assay), and the SNPs were determined by PCR-restriction fragment length polymorphism (RFLP) assay. No significant differences in the allele frequencies between cancer patients and controls for any of these four SNPs were detected. Although the initial DNA damage levels were approximately similar, significantly higher level of Fpg-sensitive sites were found in patients compared with controls (pble modulating effect of hOGG1 gene on the kinetics of strand-break rejoining was estimated. The lowest residual DNA damage level was determined in subjects with the combined APE1(Asp/Asp)/hOGG1(Ser/Cys+Cys/Cys) genotypes. Based on these preliminary data we suppose that a combination of several amino acid substitution variants of DNA repair genes involved in the same repair pathway rather than one low-penetrance SNP in a single gene may contribute to DNA repair outcomes. Larger study with more subjects is needed to verify these findings.