A large-scale multi-center analysis reveals that HNRNPA2B1 variants increase neuroblastoma risk in Chinese children

Neuroblastoma has significant clinical heterogeneity, more precise genetic biomarkers are needed for early risk stratification. Although m 6 A modification has been reported to affect tumor development, the epidemiological impact of HNRNPA2B1 polymorphisms on neuroblastoma susceptibility remains to be determined. We recruited 1300 children with neuroblastoma and 2207 cancer-free controls across 9 Chinese hospitals to investigate the genetic contribution of HNRNPA2B1 variants (rs17153396 T > A and rs4273 C > T). Genetic associations were assessed through logistic regression and stratified risk analysis, and the robustness of the results was tested by false-positive report probability (FPRP) assessments. We integrated how HNRNPA2B1 affects survival and its interactome network by combining data from two public sets (GSE45547 and GSE16476) with protein‒protein interaction (PPI) network analysis. The rs4273 C > T polymorphism increased neuroblastoma risk [adjusted odds ratio (OR) = 1.28, 95% confidence interval (CI) = 1.03–1.57, P = 0.023], and showed cumulative allelic effects (adjusted OR = 1.25, 95% CI = 1.02–1.53, P = 0.029). This genetic susceptibility was mainly manifested in female patients, infants (≤ 18 months), and early-stage patients [International Neuroblastoma Staging System (INSS) I + II+4s]. Transcriptome analyses revealed that upregulation of HNRNPA2B1 was correlated with advanced INSS stage, MYCN amplification, and poor prognosis, and its corresponding protein functioning as a critical hub in oncogenic PPI network. The rs4273 variant emerges as a novel genetic determinant of neuroblastoma risk. The association between HNRNPA2B1 abnormalities and aggressive clinical phenotypes suggest that HNRNPA2B1 is both a potential risk indicator and a promising target for neuroblastoma treatment.