Polymorphisms in genes involved in homologous recombination repair interact to increase the risk of developing acute myeloid leukemia

Purpose: Double-strand break repair via homologous recombination is essential in maintaining genetic integrity. RAD51 and XRCC3 are involved in the repair of DNA by this pathway, and polymorphisms have been identified in both the RAD51 (RAD51-G135C) and XRCC3 (XRCC3-Thr241Met) genes. The object of this study was to examine whether these polymorphisms may modulate susceptibility to the development of acute myeloid leukemia (AML), a disease that is characterized by genetic instability. Experimental Design: We studied the distribution of polymorphisms in RAD51 and XRCC3 in 216 cases of de novo AML, 51 cases of therapy-related AML (t-AML), and 186 control subjects using PCR followed by restriction enzyme digestion. The polymorphic deletion of the detoxification gene glutathione S-transferase M1 (GSTM1) was also examined by PCR. Results: The risk of the development of AML was found to be significantly increased when both variant RAD51-135C and XRCC3-241Met alleles are present [odds ratio (OR), 3.77; 95 % confidence interval (CI), 1.39 -10.24], whereas the risk of t-AML development is even higher (OR, 8.11; 95% CI, 2.22-29.68), presumably because of the large genotoxic insult these patients receive after their exposure to radiotherapy or chemotherapy. If we further divide the AML group into patients in which the burden of DNA damage is increased, because of the deletion of the GSTM1 gene, the risk of development of AML is further increased (OR, 15.26; 95% CI, 1.83-127.27). Conclusions: These results strongly suggest that DNA double-strand breaks and their repair are important in the pathogenesis of both de novo and t-AML.