ABCC2(rs717620), and ABCC3 (rs4793665) affect high dose Methotrexate
toxicity, and outcome in children with osteosarcoma
Abstract
Objectives: Osteosarcoma (OS) is one of the aggressive bone tumors
commonly diagnosed in adolescents and young adults. The study
investigated the effect of 9 single nucleotide polymorphisms (SNPs) in 5
genes on methotrexate (MTX) plasma level and its impact on the patients’
clinical outcomes. Methods: One hundred and thirty-three patients with
OS (68 boys and 65 girls with age range 4.00-17.86 years) were enrolled
and treated with four weeks of high-dose methotrexate (HDMTX) as
neo-adjuvant therapy in children’s cancer hospital (CCHE-57357). Blood
samples were collected and genotyped for the studied SNPs (MTHFR
rs1801133, SLCO1B1 rs11045879, rs4149081, rs2306283, ABCC3 rs4793665,
rs4148412, rs733392 ABCG2 rs2231142, and ABCC2 rs717620 using Taqman®
(RT-PCR) assay. Plasma concentrations of MTX were measured using the
enzyme multiple immunoassay technique (EMIT®). The clinical outcomes
included toxicities that were evaluated based on the common terminology
criteria for adverse events - version 5 (CTCAEv5.0.), besides the
studying of survival analysis and tumor necrosis (TN %). Results: Older
patients experienced increased risk of delayed MTX elimination at
72-hour, OR=1.19 (95% CI=1.09-1.29, p=0.00059). The studied SNPs
weren’t associated with MTX elimination. Patients with ABCC2 HW
(Homozygous wild) genotype group showed a high statistically significant
association with higher grade hyperbilirubinemia, OR= 2.05(95%
CI=1.05-4.01, p=0.037). Moreover, the patients with ABCC3 (rs4793665) HV
and HT (Homozygous variant and Heterozygous) genotypes had a significant
association with severe nephrotoxicity, OR= 0.34(95% CI=1.6-0.72,
p=0.005). Conclusions: ABCC2 (rs717620), ABCC3 (rs4793665) genotyping
with age and gender could help in predicting patients at risk of
toxicities due to HDMTX.