Implication of polymorphisms in DNA repair genes with an increased risk of hepatocellular carcinoma

Introduction: The frequency of alleles and genotypes of DNA repair genes in people working due to the influence of industrial aerosols (miners and workers of asbestos-cement plants (n = 215)) was studied. The aim of the work was to identify allelic polymorphisms affecting the formation of resistance or leading to an increased risk of developing bronchopulmonary pathology. Materials and methods: In 90 patients with bronchopulmonary pathology and 125 persons working under the same conditions but without respiratory system diseases, the polymerase chain reaction in real time was determined by the polymorphisms of DNA repair genes: XPD (rs13181, rs799793), ERCC1 (rs11615), XRCC1 ( rs25487) and XRCC3 (rs861539), ATM (rs664677), XRCC7 (rs7003908) and MLH1 (rs1799977). Results: In the course of this study the alleles and genotypes contributing to resistance to the development of respiratory system pathologies were determined: XRCC1•G/A (rs25487) (OR=0.57; 95% CI: 0.32-1.02; P≤0.040; χ²=4.14); MLH1•A (rs1799977) (OR=0.62; 95% CI: 0.40-0.96; P≤0.020; χ²=5.06); MLH1•A/A (rs1799977) (OR=0.43; 95% CI: 0.24-0.79; P≤0.003; χ²=8.73). Also, we established the alleles and genotypes associated with the risk of developing bronchopulmonary pathology: XPD•C/C (rs13181) (OR=2.20, 95% CI: 1.02-4.77; P≤0.020; χ²=4.85); XRCC1•A/A (rs25487) (OR=3.37; 95 % CI: 1.22-9.63; P≤0.008; χ²=6.94); ATM•T/T (rs664677) (OR=2.48; 95% CI: 1.16-5.31; Р≤0.010; χ²=6.61); MLH1•G (rs1799977) (OR=1.61; 95% CI: 1.04-2.49; P≤0.020; χ²=5.06); MLH1•A/G (rs1799977) (OR=2.32; 95% CI: 1.29-4.21; P≤0.002; χ²=9.01). Conclusions: The results indicate the influence of allelic polymorphisms of DNA repair genes on the formation of resistance to the development of bronchopulmonary pathology under the action of industrial aerosols and open up prospects for the development of modern preventive measures.

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Increased Frequency of Polymorphisms in XRCC3 and OGG1 Genes in Patients with MDS.

Blood ◽

10.1182/blood.v106.11.3445.3445 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3445-3445

Author(s):

Hadrian Szpurka ◽

Abdo Haddad ◽

Soumit Basu ◽

Mikkael Sekeres ◽

Jaroslaw P. Maciejewski

Keyword(s):

Dna Repair ◽

Genetic Factors ◽

Dose Effect ◽

Dna Repair Genes ◽

Genetic Traits ◽

Increased Risk ◽

Disease Predisposition ◽

Radiation Induced ◽

Or Gene ◽

Repair Genes

Abstract The effects of genetic factors on susceptibility to MDS are not well understood. The predisposition may be a result of complex genetic traits, various theories can explain how inherited genic sequence alterations could result in a higher susceptibility to this disease. In theory, genes involved in the metabolism of genotoxic chemicals, DNA repair genes and immunogenetic factors could all play a role. Possibly, the predisposition can be multifactorial and overall risk for MDS modified by acute or cumulative effects of environmental exposures. Alterations/variants of genes involved in MDS may result from mutations, which due to LOH or “gene dose effect” could lead to functional consequences. In addition SNPs, may be present in a variety of genes and by modifying their function result in a disease predisposition. For example, genes coding for enzymes involved in the metabolism or detoxification of cancirogens may show polymorphisms associated with low functional capacity. Based on previous reports, we have selected 4 genes for which specific SNPs have been implicated in increased risk of malignancies. Genes involved in DNA repair constitute rational targets of analysis in MDS as their dysfunction could explain increased frequency of chromosomal aberrations characteristic for this disease. For example, OGG1, XRCC1 and XRCC3 have been implicated in sensitivity to DNA damage following radiation and their variants may increase radiation-induced risk of malignancies. The NQO1 variant (involved in the protection of DNA from oxidative damage) was found to be associated with secondary AML (sAML). We have studied the frequency of homo- and heterozygous SNPs of these genes in MDS to determine whether they constitute genetic factors predisposing to MDS. Experimental cohort included 62 patients with MDS (35 RA/RS, 19 RAEB/t and 8 CMML). An allele specific Taqman PCR assay was designed to distinguish between SNPs in OGG1 (S326C), XRCC1 (R399Q), XRCC3 (T241M) and NQO1 (P187S). When XRCC3 was analyzed, C/T and T/T genotype was found in 75% of MDS patients (vs. 47% in controls; N=175; p<.001). Interestingly, 3 out of 4 patients with sAML were homozygous for the T/T genotype. When patients with RCMD were separately analyzed, 8/10 patients showed at least one allele with XRCC1 G→A SNP (80% vs. 47% p<.001). Based on historically established large cohorts of controls, we did not find an increased frequency of homo- or heterozygous variants of NQO1, XRCC1 or OGG1 in the MDS group as a whole. However, 9/12 (80%) patients with RAEB-2 showed at least one allele with C→G SNP (vs. 29% in controls, N=31). Interestingly, we have found 4 MDS (6%) patients homozygous for OGG1 variant (G/G) that has not been described in healthy controls. Three of these 4 patients had MDS/MPL overlap and one showed evolution to AML. In general, we did not find any correlation between the presence of the gene variants tested and evolution of karyotypic abnormalities. Although we have analyzed only 4 selected DNA repair genes in MDS, our findings suggest that genetically-determined decreased function of these genes may constitute a predisposition factor for the development of this disease. Increased frequency of XRCC3 C/T SNP and presence of patients homozygous for OGG1 G/G may represent examples of such susceptibility. More comprehensive analysis may reveal further polymorphisms that could alone or in context of other defects explain occurrence of MDS.

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A Polymorphism Study on Detoxification and DNA Repair Genes in 700 MDS Patients Demonstrates An Association Between Genotype and An Aberrant Karyotype

Blood ◽

10.1182/blood.v112.11.2690.2690 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2690-2690

Author(s):

C. Seedhouse ◽

Stephanie Fischer ◽

Christina Ganster ◽

Christa Fonatsch ◽

Peter Valent ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Genetic Stability ◽

Genetic Instability ◽

Dna Repair Genes ◽

Repair Gene ◽

Dna Repair Gene ◽

Increased Risk ◽

Xrcc3 Thr241met ◽

Repair Genes

Abstract The maintenance of genetic stability within haematopoietic stem cells is essential for normal haematopoiesis and this is emphasised by the association of leukemias and myelodysplastic syndromes (MDS) with genetic instability. DNA is normally protected from damage via a number of complex pathways including detoxification and DNA repair pathways. Inefficient processing of DNA damage may result in an increased susceptibility to leukemia and MDS. Genetic polymorphisms exist in many genes within the DNA damage processing pathways, some of which affect the cells ability to maintain genetic stability. We have studied polymorphisms in the homologous DNA repair genes RAD51 (RAD51-g135c) and XRCC3 (XRCC3-Thr241Met) and the detoxification gene GSTM1 (deletion polymorphism) in more 700 MDS samples. The GSTM1 polymorphism was studied using PCR, and the RAD51 and XRCC3 genotypes were assayed simultaneously using a SNaPshot technique. The genotype distributions of RAD51-g135c and GSTM1 did not differ significantly from those reported in the literature. However the distribution of the XRCC3-Thr241Met polymorphism was found to be significantly different, with an over-representation of the variant Met allele, when compared to previously published frequencies in control populations1 (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.3–2.6, p<0.001). Whilst the presence of a single polymorphic variant may display only a subtle effect, polymorphic variants of more than one gene involved in the same pathway are likely to be biologically important with respect to the cellular ability to maintain genetic integrity and hence may play a role in MDS pathogenesis. RAD51, XRCC3 and GSTM1 genotypes were therefore studied in combined analyses. Similar to studies in AML1, the double DNA repair gene variant (RAD51–135c/XRCC3–241) was over-represented in MDS compared to a control population (OR 3.8; 95% CI 1.6–9.3, p=0.002). The triple variant genotype (RAD51–135c/XRCC3–241Met/GSTM1-null) was associated with a further increased risk of MDS (OR 13.5; 95% CI 1.8–102.8, p=0.01). More detailed analysis was undertaken to compare the polymorphic distributions in MDS with aberrant karyotypes. When the single genes were assessed, the GSTM1 null genotype was the only one to be over-represented in MDS with an aberrant karyotype compared to MDS with a normal karyotype (OR 1.6; 95% CI 1.05–2.5). Interestingly, when analysing the genotypes with respect to the XRCC3/RAD51 combined genotypes the presence of homozygous wild type alleles of one DNA repair gene matched with the presence of a variant allele of the other DNA repair gene is significantly protective against karyotypic abnormalities when compared to the double WT patients (OR 0.29; 95% CI 0.29–0.78; p=0.003). Collectively these results suggest that polymorphisms in genes which process DNA damage play a significant role in MDS pathogenesis and may also contribute to genetic instability in MDS.

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