Genetic variations in base excision repair genes and the risk of developing hepatoblastoma: A five-center...

Hepatoblastoma (HB) is the most common primary liver malignancy in children. Oxidative DNA damage is primarily repaired through the base excision repair (BER) pathway, and genetic polymorphisms in BER-related genes may influence individual susceptibility to HB. However, the contribution of BER gene variants to HB risk remains unclear.

A multicenter case-control study including 193 HB patients and 773 cancer-free controls were conducted. Twenty potentially functional single nucleotide polymorphisms (SNPs) in key BER pathway genes were genotyped using TaqMan assays. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models controlling for age and sex. The Benjamini-Hochberg false discovery rate (FDR) procedure was applied to account for multiple testing in the primary analysis. Expression quantitative trait loci (eQTL) analyses were performed using publicly available GTEx data to explore potential regulatory effects.

In unadjusted analyses, several BER SNPs showed nominal associations with HB susceptibility under specific genetic models, including PARP1 rs2666428, APEX1 rs1760944, LIG3 rs4796030, XRCC1 rs25487, and XRCC1 rs915927. However, after Benjamini-Hochberg false discovery rate (FDR) correction across the 20 examined SNPs in the primary (dominant-model) analysis, none of the associations remained statistically significant at an FDR threshold of 0.05. The smallest FDR-adjusted q values were 0.053 (PARP1 rs2666428, APEX1 rs1760944, and XRCC1 rs25487), indicating borderline but non-significant signals. Stratified analyses suggested potential subgroup-specific effects, but these findings were based on limited sample sizes and should be interpreted cautiously. eQTL analyses indicated that selected variants were associated with altered gene expression in normal tissues, providing preliminary functional support.

This study provides exploratory evidence suggesting that genetic variation in BER pathway genes may contribute to HB susceptibility in Chinese children. Given the multiple testing burden and modest effect sizes, these findings should be considered hypothesis-generating and require validation in independent cohorts and functional studies.