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Impact of microRNA polymorphisms on high-dose methotrexate-related hematological toxicities in pediatric acute
Min Zhan1, Ting Liu1, Zhou Zhang1
1Department of Pharmacy, Shenzhen Children's Hospital, Shenzhen, China.
Objectives:
It is well known that transporter and enzyme genes could be regulated by microRNA (miRNA) at the post-transcriptional level, and single-nucleotide polymorphisms (SNPs) in miRNA, which are involved in the miRNA production and structure, may impact the miRNA expression level and then influence drug transport and metabolism. In this study, we aim to evaluate the association between miRNA polymorphisms and high-dose methotrexate (HD-MTX) hematological toxicities in Chinese pediatric patients with acute lymphoblastic leukemia (ALL).
Method:
A total of 181 children with ALL were administered with 654 evaluable cycles of HD-MTX. Their hematological toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5. The association between 15 candidate SNPs of miRNA and hematological toxicities (leukopenia, anemia, and thrombocytopenia) was analyzed using Fisher's exact test. Further multiple backward logistic regression analysis was used to explore the independent risk factors for grade 3/4 hematological toxicities.
Result:
Rs2114358 G>A in pre-hsa-miR-1206 was related to HD-MTX-related grade 3/4 leukopenia after multiple logistic regression [GA + AA vs. GG: odds ratio (OR): 2.308, 95% CI: 1.219-4.372, P = 0.010], and rs56103835 T > C in pre-hsa-mir-323b was associated with HD-MTX-related grade 3/4 anemia (TT + TC vs. CC: OR: 0.360, 95% CI: 0.239-0.541, P = 0.000); none of the SNPs were significantly associated with grade 3/4 thrombocytopenia. Bioinformatics tools predicted that rs2114358 G>A and rs56103835 T>C would impact the secondary structure of pre-miR-1206 and pre-miR-323b, respectively, and then probably influence the expression level of mature miRNAs and their target genes.
Conclusion:
Rs2114358 G>A and rs56103835 T>C polymorphism may potentially influence HD-MTX-related hematological toxicities, which may serve as candidate clinical biomarkers to predict grade 3/4 hematological toxicities in pediatric patients with ALL.
Insights
Single-nucleotide polymorphisms (SNPs) in microRNA (miRNA) can affect drug metabolism. Specific miRNA SNPs (rs2114358 and rs56103835) are associated with high-dose methotrexate (HD-MTX) hematological toxicities in pediatric acute lymphoblastic leukemia (ALL) patients.
Area of Science:
- Pharmacogenomics
- Molecular Biology
- Pediatric Oncology
Background:
- MicroRNAs (miRNAs) regulate gene expression post-transcriptionally, influencing drug transport and metabolism.
- Single-nucleotide polymorphisms (SNPs) in miRNAs can alter miRNA production and structure, potentially affecting drug-related toxicities.
- High-dose methotrexate (HD-MTX) is a critical treatment for acute lymphoblastic leukemia (ALL), but its use is limited by hematological toxicities.
Purpose of the Study:
- To investigate the association between miRNA polymorphisms and HD-MTX-induced hematological toxicities in Chinese pediatric ALL patients.
- To identify potential miRNA-based biomarkers for predicting severe hematological toxicities.
Main Methods:
- A cohort of 181 pediatric ALL patients receiving HD-MTX was analyzed.
- Candidate SNPs in 15 miRNAs were genotyped.
- Hematological toxicities (leukopenia, anemia, thrombocytopenia) were assessed using NCI-CTCAE v5 criteria.
- Statistical analyses included Fisher's exact test and logistic regression.
Main Results:
- The rs2114358 G>A polymorphism in pre-hsa-miR-1206 was significantly associated with an increased risk of grade 3/4 leukopenia (OR: 2.308, P=0.010).
- The rs56103835 T>C polymorphism in pre-hsa-mir-323b was associated with a reduced risk of grade 3/4 anemia (OR: 0.360, P=0.000).
- No significant association was found between the studied SNPs and grade 3/4 thrombocytopenia.
Conclusions:
- Specific miRNA polymorphisms, rs2114358 and rs56103835, may influence HD-MTX-related hematological toxicities in pediatric ALL.
- These polymorphisms show potential as predictive biomarkers for severe toxicities, aiding personalized treatment strategies.
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