Potentially Functional Variants in FCER1A and PLCG2 , Two B Cell‐Related Immune Genes Predict the Survival of Chinese Gastric Cancer Patients

ABSTRACT B cells are integral components of the tumor microenvironment (TME) and influence the progression, prognosis, and immunotherapy response of gastric cancer (GC). However, the prognostic relevance of germline variants in B cell‐related immune genes remains undefined. We performed a two‐stage genome‐wide association analysis to identify single‐nucleotide polymorphisms (SNPs) in B cell‐related immune genes associated with overall survival (OS) in patients with pathologic tumor‐node‐metastasis (pTNM) stage I–III GC. Clinical, follow‐up, and genome‐wide association study (GWAS) genotyping data were analyzed from two independent Eastern Chinese cohorts (Shanghai, N = 2211; Jiangsu, N = 1049). Functional annotation, quantitative trait loci (QTL), and immune infiltration analyses were conducted. Among 15,857 SNPs across 223 genes, 210 were associated with OS in the discovery cohort, nine of which were validated. Two independent functional variants— FCER1A rs539959920 C > T and PLCG2 rs72832034 C > T—were consistently associated with poorer OS (adjusted HR = 1.19, 95% CI = 1.04–1.37, p = 0.014; HR = 1.34, 95% CI = 1.09–1.64, p = 0.005). Patients carrying multiple unfavorable genotypes exhibited a dose‐dependent decline in survival ( P trend = 0.002). Incorporation of these SNPs modestly improved time‐dependent AUCs for OS prediction at 36 months. Single‐cell expression and splicing QTL analyses demonstrated allele‐specific modulation of FCER1A and PLCG2 expression across immune cell subsets, consistent with altered immune infiltration patterns in the GC TME. These findings suggest that two germline variants in FCER1A and PLCG2 independently predict GC survival, likely through transcriptional and immunologic modulation, thereby nominating these variants as potential immune‐genetic biomarkers for GC prognosis and therapeutic stratification.