Association of DNA damage response gene polymorphisms with treatment response and prognosis in acute myeloid leukemia

The potential functional Single Nucleotide Polymorphism (SNPs) of DNA Damage Response (DDR)-related genes may influence AML aggressiveness and clinical outcomes through regulating genomic stability. However, systematic evaluation of functionally relevant SNPs across the entire DDR cascade in AML remains limited. In our study, significant associations were identified across multiple DDR modules. In the damage sensing module, MRE11 rs2155209 TC/CC genotypes were protective against hyperleukocytosis and associated with longer OS, while NBS1 rs1805794 CG/GG genotypes increased hyperleukocytosis risk. In the signal transduction module, CHEK1 rs521102 AA genotype was a risk factor for thrombocytopenia but unexpectedly associated with prolonged OS; CHEK2 rs738722 TT genotype increased hyperleukocytosis risk; RAD17 rs1045051 GT/GG genotype conferred a higher relapse risk; and BRCA1 rs1799949 GA/AA genotype as a protective factor for high BM blast percentage. In the DNA repair module, LIG3 rs3744356 TT genotypes predicted higher WBC counts and lower complete remission rate. Both LIG3 rs3744356 TT genotype and MGMT rs2296675 GA genotype were associated with shorter OS (HR = 1.719, 95% CI = 1.082 -2.741, p = 0.022; HR = 1.511, 95% CI = 1.046 - 2.182, p = 0.028). SNPs in effector genes TP53 and CDKN1A showed no significant associations. In summary, SNPs across the DDR pathway-particularly in damage sensing, signal transduction, and DNA repair modules-are significantly associated with AML clinical features, treatment response, and survival. Our findings provide a foundation for developing DDR-based polygenic risk models and support the potential integration of germline SNP profiling into precision medicine strategies for AML.