Genetic variants in m6A regulator genes confer susceptibility and progression of HCC in a Northern Chinese population

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally. While m6A regulators are implicated in cancer progression, the role of single nucleotide polymorphisms (SNPs) in m6A regulator genes in HCC susceptibility remains underexplored. Here, we evaluated 31 candidate SNPs across eight dysregulated m6A regulator genes in a case-control study comprising 800 HCC patients and 800 healthy controls from Northeast China. Genotyping revealed three SNPs significantly associated with elevated HCC risk: rs2736158 C allele (PRRC2A; adjusted odds ratio [OR] = 1.295, 95% [CI] = 1.039-1.615, p = 0.021), rs9366785 A allele (PRRC2A; adjusted odds ratio [OR] = 1.312, 95% [CI] = 1.011-1.704, p = 0.041), and rs274054 C allele (IGF2BP3; adjusted odds ratio [OR] = 1.224, 95% [CI] = 1.040-1.440, p = 0.015). Comparison of genotype frequency of three SNPs under given genetic models further linked rs274054 CC (IGF2BP3), rs2736158 CC (PRRC2A), and rs9366785 AA + AG (PRRC2A) genotypes to higher HCC risk. Subgroup analyses identified associations between specific genotypes (e.g., rs9906944 TT/TC in IGF2BP1) and adverse clinicopathological features, including vascular invasion and liver cirrhosis. Haplotype analysis highlighted the CACA haplotype (PRRC2A: rs280801, rs2736171, rs2736158, rs2736157) as a high-susceptibility marker (adjusted odds ratio [OR] = 1.297, 95% [CI] = 1.041-1.616, p = 0.020). Our findings suggest that m6A regulator SNPs contribute to HCC susceptibility and progression, offering insights into genetic biomarkers for risk stratification in Northeast Chinese populations.