Influence of DNA repair gene polymorphisms on the yield of chromosomal aberrations

Abstract

We evaluated the influence of several DNA repair gene polymorphisms on the frequency of chromosomal aberrations (CAs) analyzed in peripheral lymphocytes, using the fluorescence in situ hybridization technique. The CA data were obtained from an earlier study of 84 healthy nonsmokers (48 women and 36 men) carefully characterized for indoor radon exposure. The frequency of translocations showed a wide interindividual variability, which was only partly explained by age. To investigate the potential role of DNA repair polymorphisms in this variation, genotypes of DNA repair genes OGG1 (codon 326), XPD (codon 751), XRCC1 (X-ray repair cross-complementing group 1) (codons 194, 280, and 399), and XRCC3 (X-ray repair cross-complementing group 3) (codon 241) were determined from leukocyte DNA using polymerase chain reaction-based methods. Negative binomial regression models were applied to evaluate the effect of the polymorphisms and other factors (age, gender, radon exposure, and medical exposure) on the frequency of CAs. No interactions between genotypes and radon, medical exposure, or gender were found. Carriers of the XRCC1 codon 280His variant allele had a two-fold increase (frequency ratio [FR] = 2.01, 95% confidence interval [CI] = 1.01-3.98; P = 0.046) in unstable exchanges (dicentrics and ring chromosomes). In addition, the XRCC3 codon 241 homozygous variant genotype (Met/Met) was associated with an increase (FR = 1.70, 95% CI = 1.06-2.74; P = 0.028) in two-way translocations when age was taken into account in the analysis. Our data suggest that the XRCC1 280His and XRCC3 241Met alleles affect individual CA levels, most probably via influencing the DNA repair phenotype.

Influence of polymorphisms at loci encoding DNA repair proteins on cancer susceptibility and G2chromosomal radiosensitivity

“…Individuals carrying XRCC3 Met241 have previously been shown to be deficient in DNA repair as attested by an increase in chromosome deletions using an in vitro cytogenetic challenge assay [Au et al, 2003] and by elevated levels of chromosomal translocations [Kiuru et al, 2005] and micronuclei [Angelini et al, 2005] following in vivo radiation exposures. However, although the present finding would appear to provide further support for an influence on DNA repair, the association between the XRCC3 Thr241Met SNP and G 2 radiosensitivity was not confirmed with FBAT analysis.…”

“…Polymorphic variation in DNA repair genes has been reported to influence the response to in vitro irradiation as measured by cell cycle delay [Hu et al, 2001], cytogenetic damage [Lunn et al, 2000;Au et al, 2003;Marcon et al, 2003], and DNA single strand break induction and repair using the Comet assay [Aka et al, 2004;Godderis et al, 2004;Rzeszowska-Wolny et al, 2005]. However, whilst variation in DNA repair gene polymorphisms has been reported to influence the in vivo frequencies of micronuclei [Angelini et al, 2005] and unstable chromosome aberrations [Kiuru et al, 2005] following low dose irradiation, no such effect was found when stable translocations were used as the endpoint [Kiuru et al, 2005;Wilding et al, 2005].…”

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

“…This finding is in agreement with data from experimental models, where the XRCC3 241 T allele (Thr/Met amino-acid variation) was found to be associated with defective DNA repair. 48,49 Notably, SN-38 specifically targets Topo I and stabilizes the Topo I-DNA complex. Collision of this complex with moving DNA replication forks causes lethal double-strand DNA breakage and cell death.…”

XRCC1 Genotype and Breast Cancer: Functional Studies and Epidemiologic Data Show Interactions between XRCC1 Codon 280 His and Smoking

“…Some laboratory investigations of XRCC1 codon 399 Gln functionality in human cells suggested that this polymorphism is associated with increased levels of DNA damage after exposure to various mutagens (17)(18)(19). Other reports offered conflicting evidence, suggesting that the 399Gln polymorphism has no adverse effect on DNA repair (20)(21)(22). The 194Trp variant protein does not seem to negatively alter the DNA repair capacity of human cells (18,20).…”