Abstract
High-dose methotrexate (HDMTX) plays an important role in the treatment of acute lymphoblastic leukemia (ALL) although there is great inter-patient variability in the efficacy and toxicity of MTX. The relationship between polymorphisms in genes encoding MTX transporters and MTX response is controversial. In the present study, 322 Chinese children with standard- and intermediate-risk ALL were genotyped for 12 polymorphisms. SLCO1B1 rs10841753 showed a significant association with plasma MTX levels at 48 h (P = 0.017). Patients who had the ABCB1 rs1128503 C allele had longer duration of hospitalization than did those with the TT genotype (P = 0.006). No association was found between oral mucositis and any polymorphism. Long-term outcome was worse in patients with the SLCO1B1 rs4149056 CC genotype than in patients with TT or TC (5-year event-free survival [EFS] 33.3 ± 19.2% vs. 90.5 ± 1.7%, P < 0.001), and was worse in patients with the SCL19A1 rs2838958 AA genotype than in patients with AG or GG (5-year EFS 78.5 ± 4.6% vs. 92.2 ± 1.8%, P = 0.008). Multiple Cox regression analyses revealed associations of minimal residual disease (MRD) at day 33 (hazard ratio 3.458; P = 0.002), MRD at day 78 (hazard ratio 6.330; P = 0.001), SLCO1B1 rs4149056 (hazard ratio 12.242; P < 0.001), and SCL19A1 rs2838958 (hazard ratio 2.324; P = 0.019) with EFS. Our findings show that polymorphisms in genes encoding MTX transporters substantially influence the kinetics and response to HDMTX therapy in childhood ALL.
Highlights
Methotrexate (MTX) has been widely used as an anticancer agent in most chemotherapy protocols for childhood acute lymphoblastic leukemia (ALL)
Previous www.impactjournals.com/oncotarget studies suggest that variations in single nucleotide polymorphisms (SNPs) of genes encoding MTX transporters play a great role in ALL prognosis and MTX response [9,10,11,12,13,14,15], but the results are inconsistent, which might result from small study cohorts, heterogeneous study populations, and differences in treatment protocols
ABC subfamily B member 1 (ABCB1) rs2032582 was excluded from the following analyses because its allele frequencies deviated from Hardy-Weinberg equilibrium (HWE)
Summary
Methotrexate (MTX) has been widely used as an anticancer agent in most chemotherapy protocols for childhood acute lymphoblastic leukemia (ALL). MTX pharmacokinetics, efficacy, and toxicity have great inter-patient variability. This diversity can be partly explained by sequence differences in genes encoding MTX membrane transporter proteins [4,5,6]. MTX enters the cell via the solute carrier family 19 member 1 (SLC19A1) or the solute carrier organic anion transporter 1B1 (SLCO1B1) [7, 8]. It is exported from the cells by ATP binding cassette (ABC) transporters, including ABC subfamily B member 1 (ABCB1), and ABC subfamily G member 2 (ABCG2) [4]. Previous www.impactjournals.com/oncotarget studies suggest that variations in single nucleotide polymorphisms (SNPs) of genes encoding MTX transporters play a great role in ALL prognosis and MTX response [9,10,11,12,13,14,15], but the results are inconsistent, which might result from small study cohorts, heterogeneous study populations, and differences in treatment protocols
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