Association of DNA repair gene XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) polymorphisms with the risk of Chronic Myeloid Leukemia: A case-control study in South Indian Population.

BACKGROUND XPC, a DNA repair protein, plays an important role in the maintenance of genomic integrity and is essential for NER pathway. Polymorphisms in XPC gene may alter DNA repair leading to genetic instability and oncogenesis. The objective of the present study was to assess the relationship between the XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) non-synonymous polymorphisms and susceptibility to CML pathogenesis, disease progression, and response to targeted therapeutic regimen, Imatinib Mesylate. METHODS This case-control study included 212 cases and 212 controls, and the genotypes were determined by PCR-RFLP assays. RESULTS Our results showed significant association of variant CT (OR= 1.92, 95% CI= 1.21-3.06, p= 0.003) and TT (OR= 2.84, 95%CI= 1.22-6.71, p= 0.007) genotypes in patients with XPC Ala499Val polymorphism and CML risk. In addition, these genotypes were associated with CML progression to advanced phases (p= 0.006), splenomegaly (p= 0.017), and abnormal LDH levels (p= 0.03). XPC Lys939Gln was found to correlate with poor response to therapy, showed borderline significant association with minor cytogenetic response (p= 0.08), and poor molecular response (p= 0.06). Significant association of Ala499Val and Lys939Gln polymorphisms with prognosis was observed (Hasford high risk, p= 0.031; 0.019). Haplotype analysis showed strong correlation of variant TC haplotype with poor therapy responses (minor CyR, p= 0.019; poor MoR, p<0.0001). CONCLUSION In conclusion, our results suggest that XPC Ala499Val is a high-penetrance CML susceptibility polymorphism. Both polymorphisms studied are considered as genetic markers in assessing disease progression, therapy response and prognosis in CML patients.