Polymorphisms in Detoxification and DNA Repair Genes in Myelodysplastic Syndromes.

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 384 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 both control and AML populations¹ (Pearson Chi-square p=0.001 and 0.016 respectively). The MDS samples were further stratified with respect to FAB groups and cytogenetics. No associations were found between any of the three genetic polymorphisms and FAB type. Interestingly the XRCC3-Met variant genotype was significantly more common in MDS samples with normal karyotypes compared to aberrant karyotypes (Pearson Chi-square p=0.01). 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. The triple variant genotype (RAD51-135c/XRCC3-241Met/GSTM1-null) occurred in 4.5% of MDS patients compared to 0.6% of healthy controls¹ (p=0.01) implicating this genotype in MDS. Collectively these results suggest that polymorphisms in genes which process DNA damage play an important role in MDS pathogenesis, a role which may be more significant in the absence of competing karyotype alterations. ¹ Seedhouse C, Faulkner R, Ashraf N, Das-Gupta E, Russell N. Polymorphisms in genes involved in homologous recombination repair interact to increase the risk of developing acute myeloid leukemia.