Clinical and biological significance of a - 73A > C variation in the CDH1 promoter of patients with sporadic gastric carcinoma.

BACKGROUND

CDH1 germline mutations lead to hereditary diffuse gastric carcinomas. However, it is unclear whether genetic variations in the CDH1 promoter affect the progression of sporadic gastric carcinomas (SGCs).

METHODS

SGC patients in two independent cohorts with follow-up data were enrolled. The CDH1 genotypes, including the - 73A > C polymorphism (rs28372783), were determined by PCR sequencing. The CDH1 promoter activity was determined using reporter assays. SNAIL bound to CDH1 alleles was determined by chromatin immunoprecipitation primer extension PCR. CDH1 DNA methylation was determined by bisulfite-based PCR analyses.

RESULTS

Kaplan-Meier analyses showed that the overall survival (OS) of the - 73C/C patients was significantly longer than that of the - 73A/C or - 73A/A patients in a Chinese cohort [n = 526; hazard ratio 0.68 (95% CI 0.47-1.00)], which was validated in an independent Korea cohort [n = 215; hazard ratio 0.49 (95% CI 0.26-0.94)]. Moreover, the transcription activity of the - 73C alleles was significantly higher than that of the - 73A alleles in vitro and in vivo. The ratio of SNAIL recruited to the promoter regions of the - 73C and - 73A alleles was 1:10, indicating a strong influence of this polymorphism on the recruitment of SNAIL to the flanking E-box. The prevalence of DNA methylation of the CpG island and shore within the promoter of the - 73C allele was much less than that of the - 73A allele in both gastric tissues and cancer cell lines.

CONCLUSION

The - 73A > C variation may lead to differences in the overall survival of SGC patients and allele-specific repressions of CDH1.