Abstract
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.
Highlights
ERBBs or epidermal growth factor receptors (EGFRs) belong to the receptor tyrosine kinase (RTK) superfamily and are important signaling proteins in normal physiological conditions [1,2]
Among the gastric cancer (GC)-associated genes, GNAI3, MAP2K1, FYN, and MAPK8 were associated with GCA, and MAPK8, TLN1, RPS6KB2, MAP2K4, and PIK3R3 were associated with GNCA (P,0.05)
Recent genome-wide association studies (GWAS) have identified numerous risk loci associated with esophageal squamous cell carcinoma (ESCC) or GC, but far, there has been no evidence for an association with genetic variants in EGFR pathway
Summary
ERBBs or epidermal growth factor receptors (EGFRs) belong to the receptor tyrosine kinase (RTK) superfamily and are important signaling proteins in normal physiological conditions [1,2]. Ligand-bound EGFRs are regulators of cell-cycle progression, proliferation, survival, invasion, and other cancer contributing processes [3,4]. In regards to esophageal and gastric cancer, higher EGFR and ERBB2 levels have been correlated with poor esophageal and gastric cancer survival [4,6,7]. Therapies targeting the EGFR family were shown to improve esophageal and gastric cancer prognosis [4]. Several studies have revealed somatic mutations of genes in the EGFR family in esophageal and gastric cancers [8,9,10,11,12]. A role for downstream signaling of the EGFR family has been found, with molecules involved in the MAPK/ERK pathway activated in esophageal and gastric cancers [13,14,15]
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