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The epidermal growth factor receptor (EGFR) signaling pathway regulates cell proliferation, differentiation, and survival, and is frequently dysregulated in esophageal and gastric cancers. Few studies have comprehensively examined the association between germline genetic variants in the EGFR pathway and risk of esophageal and gastric cancers. Based on a genome-wide association study in a Han Chinese population, we examined 3443 SNPs in 127 genes in the EGFR pathway for 1942 esophageal squamous cell carcinomas (ESCCs), 1758 gastric cancers (GCs), and 2111 controls. SNP-level analyses were conducted using logistic regression models. We applied the resampling-based adaptive rank truncated product approach to determine the gene- and pathway-level associations. The EGFR pathway was significantly associated with GC risk ( P  = 2.16×10 −3 ). Gene-level analyses found 10 genes to be associated with GC, including  FYN ,  MAPK8 ,  MAP2K4 ,  GNAI3 ,  MAP2K1 ,  TLN1 ,  PRLR ,  PLCG2 ,  RPS6KB2 , and  PIK3R3  ( P <0.05). For ESCC, we did not observe a significant pathway-level association ( P  = 0.72), but gene-level analyses suggested associations between  GNAI3 ,  CHRNE ,  PAK4 ,  WASL , and  ITCH , and ESCC ( P <0.05). Our data suggest an association between specific genes in the EGFR signaling pathway and risk of GC and ESCC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.

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Genetic Variants in Epidermal Growth Factor Receptor Pathway Genes and Risk of Esophageal Squamous Cell Carcinoma and Gastric Cancer in a Chinese Population