Association of XRCC5 VNTR polymorphism with the development of chronic myeloid leukemia

Double-strand breaks (DSBs) inducing agents influence the fidelity of DNA repair in both normal cells and leukemic cells, causing major genomic instability. In eukaryotic cells, non-homologous end joining pathway (NHEJ) is the major mechanism for DSB repair. Human X-ray repair cross-complementing 5 (XRCC5) gene encodes for the protein KU86, an important component of NHEJ pathway. Variable number of tandem repeats (VNTR) polymorphism (rs 6147172) in the promoter region of XRCC5 gene was shown to have effect on gene expression and was found to be associated with the development of several cancers. We analyzed VNTR polymorphism of XRCC5 gene in 461 chronic myeloid leukemia (CML) cases and 408 controls by polymerase chain reaction. Our results showed that frequency of 0R/0R genotype was significantly elevated in CML cases compared to that of controls (p = 0.05). Significant difference in the genotype distribution was observed between cases and controls (p = 0.02). The risk of CML development was found to be elevated for individuals carrying lower repeats (1R p = 0.03; 0R p = 0.007). Elevated 0R/0R genotype frequency was found to be significantly associated with early age at onset (≤ 30 years) and slightly elevated in chronic phase and poor hematologic response to imatinib mesylate. The influence of zero repeat on enhanced expression of XRCC5 might confer risk to error-prone repair leading to genomic instability and CML. Hence, the VNTR polymorphism in the promoter region of XRCC5 gene could serve as an important prognostic marker in CML development.