Investigating the association of NBN gene polymorphisms with multiple cancers through statistical meta-analysis and bioinformatics insights.

Several individual genetic association studies, including meta-analyses, have investigated the association of two SNPs (rs1805794 and rs709816) of NBN gene with multiple cancer risks. However, their findings were inconsistent, making it challenging to use NBN gene as a diagnostic and prognostic biomarker. This study aims to provide an improved reliability on the association between NBN polymorphisms and multiple cancers through the extended statistical meta-analysis. We collected a comprehensive dataset comprising 58 individual SNP-cancer association studies, including 23 494 cases and 29 592 controls for rs1805794, and 5325 cases and 11 149 controls for rs709816 polymorphisms, using a systematic search strategy across online databases. The collected data were analyzed using statistical meta-analysis to investigate the association between two SNPs and cancers. This meta-analysis revealed that the allele of rs1805794 and rs709816 polymorphisms is not significantly associated with overall cancer risk in each ethnic population. However, sub-group analysis based on cancer types showed that rs1805794 is significantly associated with the increased risk of bladder cancer under three, and nasopharyngeal cancer (subtype of head and neck cancer) under four genetic models. Also, it was seen that rs1805794 is partially associated with brain cancer risk under allelic model, while rs709816 is significantly linked to breast cancer. Notably, rs1805794 exhibited a trend toward increased cancer risk, while rs709816 showed a protective tendency. Besides, bioinformatics analysis results also supported the meta-analysis results from different viewpoints including expression analysis of NBN gene from TCGA database, disease-gene and gene-regulator network analysis, and gene ontology and pathway enrichment analysis, and indicate the NBN gene directly/indirectly associated with cancer risks. Meta-analysis results, supported by bioinformatics analyses, indicate potential associations between NBN gene variants and susceptibility to bladder, brain, breast, and nasopharyngeal cancers. However, these findings are exploratory and indicate biological relevance rather than established diagnostic or prognostic utility. Systematic review registration: https://www.crd.york.ac.uk/prospero/; identifier: CRD420251034651.