Abstract 3858: Genetic polymorphisms of DNA repair genes in the origin and progression of chronic myeloid leukemia

Abstract

Abstract Background: The origin of Chronic Myeloid Leukaemia (CML) involves the formation of Double Strand Breaks (DSBs) which are initially sensed by the Ataxia Telangiectasia Mutated (ATM) signal kinase. Additionally, Bcr-Abl transformed CML cells produce high levels of Reactive Oxygen Species (ROS) that induce more DSBs. In such kind of cells, proper functioning of ATM and NHEJ repair mechanisms are required for ensuring the accurate repair of DSBs. Aim: The present study is planned to understand the role of DNA repair, specifically NHEJ repair in the occurrence of CML and its progression. Methodology: We have analysed seven genetic polymorphisms in ATM, XRCC5, XRCC6 and XRCC7 genes in 476 Ph+ve CML cases and 449 age and sex matched controls without family history of cancers. Direct Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) analyses were carried out using the DNA isolated from blood samples through non-enzymatic/salting out method. Statistical analyses were performed through SPSS (IBM SPSS Statistics 20) software. Results: The T allele of ATM C4138T polymorphism and A allele of ATM -5144A>T polymorphism were found to be significantly associated with enhanced risk of CML in our study. The CC genotype of XRCC6 -61C>G polymorphism was found to have independent effect with CML risk as confirmed by the LD and MDR analyses. Lower repeat (0R) of XRCC5 VNTR and TT genotype of XRCC7 6721G>T polymorphisms had shown borderline association with CML risk. Even though the XRCC5 2408G>A and XRCC6 -1310C>G polymorphisms did not show significant association with CML independently, the AA and GG genotypes of these polymorphisms have been found to confer enhanced risk for CML in combination with other SNPs of the respective genes in haplotype analysis. Interestingly, combined analysis demonstrated cumulative effect of risk genotypes in CML development as well as progression where the fold change increased with the number of adverse genotypes. Conclusion: The risk associated genotypes were known to influence the expression and functioning of genes in NHEJ pathway. Therefore, results of the present study suggested that defective DNA damage sensing and deregulated repair due to variations in ATM and NHEJ genes might influence CML development as well as progression. Key words: CML, ATM, NHEJ, DNA repair, polymorphisms Citation Format: Manjula Gorre, Prajitha Edathara Mohandas, Sailaja Kagita, Anuradha Cingeetham, Sugunakar Vuree, Sandhya Annamaneni, Raghunadharao Digumarti, Vishnupriya Satti. Genetic polymorphisms of DNA repair genes in the origin and progression of chronic myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3858. doi:10.1158/1538-7445.AM2015-3858