Genetic Variant at 6p21.1 Impairs APOBEC2 in Hypoxic Mitophagy via HIF-1α/BNIP3 in Gastric Cancer.

Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) at the 6p21.1 locus associated with gastric cancer (GC) risk. However, the underlying biological mechanisms remain poorly understood. We conducted fine-mapping analysis of the 6p21.1 region using large-scale GC GWAS data (10,254 cases and 10,914 controls). Functional annotation, luciferase reporter assays, Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) experiments were performed to identify functional variants. The eQTL and colocalization analyses were used to determine the susceptibility gene. Mechanistic investigations included phenotypic assays under normoxic and hypoxic conditions, along with seahorse, immunofluorescence and ATP assays to assess mitochondrial function. We identified rs9381024 as the independent association signal at 6p21.1, with rs2235679, in strong linkage disequilibrium with rs9381024, emerging as a potential causative SNP. The T risk allele of rs2235679 reduced APOBEC2 expression by enhancing the binding of transcriptional repressor MZF1, thereby suppressing promoter activity. Expression analysis revealed a progressive decrease in APOBEC2 levels with gastric lesions severity, becoming nearly undetectable in GC tissues. Functionally, reduced APOBEC2 expression significantly promoted the proliferation of GC cells under hypoxic conditions but not under normoxia. Mechanistically, downregulation of APOBEC2 activated mitophagy to maintain mitochondria homeostasis via HIF-1α/BNIP3 pathway under hypoxia, ultimately driving tumor growth. Our findings provide novel mechanistic insights into how genetic variants at 6p21.1 contribute to GC risk and progression, highlighting the tumor-suppressive role of APOBEC2.