Association of genetic variants in m¹A modification core genes and neuroblastoma risk

Neuroblastoma tightly linked with genetic abnormality. The core genes responsible for RNA N¹-methyladenosine (m¹A) modification are critical in tumor development. Nevertheless, few reports revealed the function of m¹A modification core gene polymorphisms and the neuroblastoma risk. We carried out this study to verify the association of 12 single-nucleotide polymorphisms (SNPs) with neuroblastoma susceptibility. This study recruited 898 cases with newly diagnosed neuroblastoma and 1734 Healthy controls from eight medical centers. We selected 12 SNPs from m¹A modification genes ALKBH1, TRMT6, TRMT61B, and TRMT10C, and genotypes were determined by the TaqMan method. We used univariable and multivariable logistic regression models to analyze the association of SNPs with neuroblastoma risk, followed by stratified analysis. Statistical analysis showed that TRMT6 rs236170 GG (AOR = 1.23, 95% CI = 1.02-1.50, P = 0.034), rs451571 CC (AOR = 1.46, 95% CI = 1.01-2.11, P = 0.043), rs236188 AA (AOR = 2.65, 95% CI = 1.16-6.07, P = 0.021), rs236110 AA (AOR = 1.91, 95% CI = 1.29-2.82, P = 0.001), and ALKBH1 rs6494 AA (AOR = 4.27, 95% CI = 1.31-13.93, P = 0.016), rs176942 GG (AOR = 1.98, 95% CI = 1.35-2.89, P = 0.0005) were neuroblastoma risk variants; the ALKBH1 rs1048147 CC (AOR = 0.80, 95% CI = 0.68-0.94, P = 0.007) was inverse associated with neuroblastoma risk. The eQTL analysis showed that functional annotation of rs6494 T > A may be potential function variants through decreasing ALKBH1 gene expression mRNA, rs451571 T > C, rs236188 G > A, rs236110 C > A are associated with neuroblastoma risk through increasing the expression of its nearby genes RP5-967N21.11 and lowering the expression of MCM8. Our research showed some SNPs in the m¹A modification core genes are related to neuroblastoma.Clinical perspectives(i) Few reports have revealed the function of m¹A modification core gene polymorphisms in neuroblastoma risk.(ii) After genotyping 12 SNPs with potential functions in four m¹A modification core genes in children with neuroblastoma and healthy controls, we found several neuroblastoma predisposition loci, including TRMT6 rs236170, rs451571, rs236188, rs236110, and ALKBH1 rs6494, rs176942, and rs1048147. The eQTL assessment demonstrated that rs6494 T > A may be a potential functional variant by decreasing ALKBH1 mRNA expression.(iii) Our research is the first to reveal m¹A modification core gene SNPs and neuroblastoma risk.