Comprehensive analysis of haplotypes of E-cadherin promoter and the risk of gastric cancer in China

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Frequent mutations and diminished expression of E-cadherin have been reported in a number of cancers. E-cadherin germline mutations lead to high risk of familial diffuse gastric cancer. Recently, two frequent polymorphisms (-160C→A and -347G→GA) were found to be correlated with the risk of human cancers including stomach carcinoma. However, conflict results were also reported. A comprehensive survey on large scale is necessary. In present study, we sequenced the full promoter, exon-1, and part intron-1 region of E-cadherin (-437~+314 from transcription start site). Genotypes of E-cadherin promoter of 690 cases with gastric cancer and 1021 non-malignant controls were analyzed by direct sequencing, to investigate the relationship between genotypes and haplotypes of E-cadherin promoter and the risk of gastric cancer. A novel 13-bp deletion [agccccgtgccc] at position +230 was discovered, in addition to the known -347G→GA, -160C→A, -73A→C and +178T→C polymorphisms. The 13-bp deletion was in intro-1 and linked with -347GA insertion completely (D’=1.0, r2=0.998). All polymorphisms are in strong linkage disequilibrium (LD) with each other in both patient and control groups. The haplotype analyses showed significant differences between cases and controls. The haplotype “GA_(-347)-C_(-160)-A_(-73)-T₍₊₁₇₈₎-del₍₊₂₃₀₎” was correlated with the increased risk of gastric cancer (9.3% vs 7.4%, p=0.047, OR=1.28, 95% CI: 1.00-1.64), and the haplotype “GA_(-347)-C_(-160)-A_(-73)-C₍₊₁₇₈₎-del₍₊₂₃₀₎” was a protective factor (16.6% vs 19.5%, p=0.025, OR=0.82, 95% CI: 0.68-0.98). However, no significant differences were found in the genotypes of each polymorphism between gastric cancer cases and controls when they were analyzed individually (Table). These genotypes were not correlated with clinical characteristics of gastric cancer (such as location, histology, stage, metastasis) either. In conclusion, the present data suggests that polymorphisms of E-cadherin promoter may affect the risk of gastric cancer by linked pattern only.