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

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.