Variant genotypes and haplotypes of the epidermal growth factor gene promoter are associated with a decreased risk of gastric cancer in a high‐risk Chinese population

Abstract

Epidermal growth factor (EGF), a ligand of the EGF receptor, plays a critical role in the development of gastric cancer. Genetic variants in its promoter region may influence transcription activity and contribute to gastric cancer predisposition. To test this hypothesis, we genotyped three EGF promoter polymorphisms (G61A, G-1380A, and A-1744G) in a case-control study of 675 gastric cancer cases and 704 cancer-free controls. We found that the variant genotypes of EGF 61GA/AA were associated with a significantly decreased risk of gastric cancer (OR = 0.77, 95% CI = 0.61-0.95), when compared with wild-type homozygote 61GG. In the combined analysis with all three loci of EGF, subjects carrying one or more variant loci had a significantly decreased risk of gastric cancer in a dose-response manner ( G astric cancer is the second leading cause of cancer-related mortality worldwide, accounting for ~700 000 deaths annually.(1) Almost 40% of the gastric cancer cases occur in China with a remarkable geographic variation.(2) Epidemiological studies suggest that some environmental exposures (e.g. salty diet, tobacco smoking and Helicobacter pylori infection) are important for the development of gastric cancer.(3,4) However, accumulating evidence indicates that host factors and genetic alterations may also play an important role in gastric carcinogenesis through gene-environment interactions. The EGF gene encodes a ligand for the EGFR, a receptor of tyrosine kinase. When binding with EGFR, EGF can activate multiple signaling pathways, regulating cell proliferation and differentiation.(6-9) Studies showed that EGF and EGFR were highly expressed in gastric cancer, (10,11) cooperating with H. pylori and inflammatory cytokines in gastric carcinogenesis. (12,13) Shahbazi et al. analyzed the EGF gene region from position -1350 to 164 and identified a G to A substitution at position 61 in the 5′ untranslated region, where the presence of the variant 61 A allele leads to a decreased in vitro EGF production in peripheral blood mononuclear cells. (14) Therefore, it was hypothesized that this promoter variant might be associated with risk of gastric cancer. In a hospital-based case-control study in Japan (200 cases and 230 controls), Hanai et al. reported that EGF G61A (rs4444903) was involved not only in the occurrence but also in the progression of gastric cancer.(15) However, this result was not supported by a later study in Japan (202 cases and 454 controls), although the main effect of EGF G61A was in the same direction. (16) Because the single locus may not represent the functional region of the gene promoter, it is biologically possible that other promoter variants may be also involved in gastric cancer susceptibility through a haplotype effect. Therefore, we used the public SNP database (http://www.ncbi.nlm.nih.gov/) to select SNPs in the promoter region of EGF. Apart from G61A, we chose two SNPs, G-1380A (rs11568835) and A-1744G (rs3756261), with a minor allele frequency >0.05 in a Chinese population.To evaluate the effects of...

A functional epidermal growth factor (EGF) polymorphism, EGF serum levels and renal cell carcinoma risk in a Chinese population

“…19,20 Moreover, this regulation varies according to the arrangements of ligand-receptor engagement, tyrosine phosphorylation and subsequent receptor dimerization We also analyzed the distribution of EGF genotypes among the East Asian population and Caucasian population from the previous studies, and found that, the EGF genotypes were significantly different between the East Asian population and Caucasian population. In this study, the EGF 61A allele frequency (0.273) in control was close to that reported in the Chinese (0.297, 0.305), 14,24 Korean (0.284) 25 and Japanese populations (0.313, 0.304), 12,13 but was significantly lower than that in the Caucasians (higher than 0.500). 10,11,26,27 Therefore, we confirmed that EGF genotypes were significantly different between the East Asian and Caucasian populations.…”

Cell proliferation-related genetic polymorphisms and gastric cancer risk: systematic review and meta-analysis

“…Polymorphisms determining higher level of growth factors and related receptors, which are important to tissue repair, were associated with reduced risk of GC. Such associations were observed for EGF 5 0 UTR 61G4A, 56,58 TGFB1 -509C4T, 60 TGFBR2 -875G4A, 60 and IGFBP3 -202A4C 65 and Gly32Ala. 66 PGC was reported to not only act as a digestive enzyme, but might also be a growth factor during the healing of gastric lesions.…”

EGF promoter SNPs, plasma EGF levels and risk of breast cancer in Chinese women

“…Previously, Shahbazi et al identified a G-to-A substitution at position 61 in the promoter region of EGF, and the presence of the variant 61A allele led to a decreased EGF production in peripheral blood mononuclear cells and decreased susceptibility of malignant melanoma [16]. In a case-control study of 675 gastric cancer cases and 704 cancer-free controls, we also found that the variant genotypes of EGF 61GA/AA genotypes were associated with a significantly decreased risk of gastric cancer as compared with 61GG genotype [17].…”

“…The EGF G61A was genotyped by the PCR-RFLP assay and the G-1380A and A-1744G variants were genotyped using a PIRA-PCR assay as we previously reported [17]. The PCR primers for the three loci (G61A, G-1380A, and A-1744G) were 5 0 -TGTCACTAAAGG AAAGGAGGT-3 0 (sense), 5 0 -TTCACAGAGTTTAACAG CCC-3 0 (antisense) for G61A; 5 0 -CCTTCCATTGCTGT CATCCG-3 0 (sense), 5 0 -CATTGCTTTCTGGACTGAGT CAGA-3 0 (antisense) for G-1380A; and 5 0 -AGAGCTAC CCAACTGGGAAGGATCT-3 0 (sense), 5 0 -GGCCTCGA TGCGCTTCCGCTTCA-3 0 (antisense) for A-1744G, and the restriction enzymes were AluI, HpaII, and PstI, respectively.…”