Influence of dihydrofolate reductase gene polymorphisms rs408626 (-317A>G) and rs442767 (-680C>A) on the outcome of methotrexate-based maintenance therapy in South Indian patients with acute lymphoblastic leukemia.

Abstract

The most common cause of treatment failure in acute lymphoblastic leukaemia (ALL) is the relapse. Genetic polymorphisms of dihydrofolate reductase (DHFR) enzyme affect the response to methotrexate (MTX) treatment. Inter-individual variability exists in the distribution of DHFR variants, and they influence MTX treatment outcome. To the best of our knowledge, there are no genetic studies reported from India, which have explored the influence of DHFR variants on the outcome of MTX treatment. Therefore, we aim to study the influence of DHFR rs408626 (-317A>G) and rs442767 (-680C>A) variants on ALL outcome in South Indian patients. A total of 70 ALL patients who were on MTX-based maintenance therapy were recruited for the study. DNA was extracted from leukocytes, and genotyping was done by real-time PCR. The DHFR-317GG genotype was associated with the increased risk of relapse in patients with ALL (relative risk 2.25, 95% confidence interval (CI) 1.38 to 3.6, p = 0.02). DHFR-317AA and -680CA genotypes were found to be associated with severe leucopenia (p < 0.05). In Cox regression model, -317GG genotype was found to have lower relapse-free survival (hazard ratio (HR) 2.56, 95% CI 1.06 to 6.19, p = 0.03) and overall survival (HR 3.72, 95% CI 1.44 to 9.65, p = 0.007). Similarly, patients with white blood cell (WBC) count >50,000 cells/mm(3) were also found to have lower relapse-free survival (HR 2.20, 95% CI 1.10 to 4.79, p = 0.04) and overall survival (HR 3.30, 95% CI 1.45 to 7.53, p = 0.004). The GG genotype of DHFR-317A>G variant is associated with increased risk of ALL relapse and lower overall survival in South Indian population. Both variants of DHFR (-317 AA and -680 CA) are found to be associated with severe leucopenia caused by MTX.