Genetic Variants in METTL14 are Associated with the Risk of Acute Lymphoblastic Leukemia in Southern Chinese Children: A Five-Center Case-Control Study

Abstract

Background/Aim

Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer. METTL14, an N⁶-methyladenosine (m⁶A) modification protein, plays several roles in cancer development and is involved in the pathogenesis of various types of cancers. However, the role of METTL14 gene single nucleotide polymorphisms (SNPs) in pediatric ALL susceptibility remains to be investigated.

Methods

A case-control design and multinomial logistic regression were used to develop models to estimate the overall risk for pediatric ALL and three METTL14 gene SNPs (rs298982 G/A, rs298981 A/G and rs1064034 T/A) in 808 cases and 1340 controls, which were genotyped using a TaqMan assay. The associations were estimated by odds ratios (ORs) with their 95% confidence intervals (CIs). Furthermore, stratified analysis was performed to explore associations of rs298982 and rs1064034 with pediatric ALL susceptibility in terms of age, sex, immunophenotype, minimal residual disease (MRD), and other clinical characteristics.

Results

Among the three analyzed SNPs, rs298982 G/A and rs1064034 T/A exhibited a significant association with decreased childhood ALL risk, while rs298981 A/G exhibited no difference. In stratified analysis, rs298982 GA/AA and rs1064034 TA/AA had a protective effect in children <120 months of age and males, common B ALL, TEL-AML, non gene fusion, normal diploid, and high WBC. However, the rs1064034 TA/AA genotype was associated with an increased risk of mixed immunophenotyping. Compared with the reference haplotype GAT, haplotypes CAA, CGT and CGA were significantly associated with elevated ALL risk, while haplotype GGT was significantly associated decreased ALL risk. Moreover, subjects carrying rs298982 A or rs1064034 A exhibited less minimal MRD after induced chemotherapy. Functional annotations revealed that METTL14 gene SNPs rs298982 G/A and rs1064034 T/A could be potential functional variants.

Conclusion

In conclusion, METTL14 gene polymorphisms influence the risk of ALL in southern Chinese children and might be potential biomarkers for pediatric ALL susceptibility and chemotherapeutics.

Keywords:

• ALL
• METTL14
• SNP
• susceptibility
• Chinese children

Acknowledgments

We thank the Clinical Biological Resource Bank of Guangzhou Women and Children’s Medical Center for providing some of the clinical samples.

Abbreviations

METTL14, methyltransferase like 14; ALL, acute lymphoblastic leukemia; m⁶A, N6-methyladenosine; SNPs, single nucleotide polymorphisms; ORs, odds ratios; CIs confidence intervals; MRD, minimal residual disease; B-ALL, B-cell precursor acute lymphoblastic leukemia; T-ALL, T-cell lineages acute lymphoblastic leukemia; ARID5B, AT-rich interaction domain 5B; USP1, ubiquitin specific peptidase 1; METTL3, methyltransferase 3; WTAP, WT1 associated protein; FTO, fat mass and obesity-associated protein; ALKBH5, α-ketoglutarate-dependent dioxygenase homolog 5; SYSU, Sun Yat-sen University; GTEx, the Genotype-Tissue Expression; FPRP, false-positive report probability; AML, acute myelocytic leukemia; CCCG, Chinese Children Cancer Group chemotherapeutics; SCCLG, South China Children Leukemia Group chemotherapeutics; eQTL, expression quantitative trait loci; mRNA, messenger RNA; lncRNA, long noncoding RNA; SNHG8, small nucleolar RNA host gene 8.

Ethics Approval and Consent to Participate

The experiments were approved by the Ethics Committee of the Guangzhou Women and Children’s Medical Center. Written informed consent was obtained from all patients. The experiments were carried out following the Declaration of Helsinki.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, agreed to the submitted journal, and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest in this work.