Influence of Dihydrofolate Reducatse (DHFR) Gene Polymorphisms on Outcome of Methotrexate Maintenance Therapy in Patients with Acute Lymphoblastic Leukemia

Objectives: 1)To determine the influence of DHFR gene polymorphisms on outcome of methotrexate-based maintenance therapy in patients with acute lymphoblastic leukemia (ALL) 2)To compare the relapse free survival between DHFR genotype 3)To establish the normal allele and genotype frequencies of the DHFR polymorphisms in the South Indian population Methods: A total of thirty one patients with ALL were included for the study. A total of 85 healthy volunteers from the South India were recruited to establish the allelic frequencies of the A-317G & C-680A variants of DHFR gene. DNA was extracted by phenol chloroform method and genotyping was done by allelic discrimination method. Patients were followed up for two years for the outcome. Results: Homozygous mutant genotype carriers (GG) were at two-fold increased risk of relapse when compared to the other genotypes (AA & AG) [Relative risk= 2.6; 95% CI, 1.260 to 5.365, P<0.05]. Relapse-free survival rate was lower in GG genotype carriers when compared to wild and hetero genotypes [Log-rank test, p<0.05]. The genotype frequencies of A-317G variant in healthy volunteers were- AA=51.76%, AG=37.64%, GG=10.58% and C-608A variant genotype frequency were-CC=0%, AC=20.98%, AA=79.01%. Conclusion: GG variant of DHFR A-317G is associated with increased relapse and lower relapse-free survival in ALL patients.