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

Baozhen Zhang, Jing Zhou, Zhaojun Liu, Liankun Gu, Jiafu Ji, Woo Ho Kim, Dajun Deng

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)606-616
Number of pages11
JournalGastric Cancer
Volume21
Issue number4
DOIs
StatePublished - 1 Jul 2018

Fingerprint

Stomach
Alleles
Carcinoma
DNA Methylation
Polymerase Chain Reaction
CpG Islands
Survival
Germ-Line Mutation
Chromatin Immunoprecipitation
Korea
Genetic Promoter Regions
Stomach Neoplasms
Genotype
Cell Line

Keywords

  • Allele-specific repression
  • CDH1
  • DNA methylation
  • Gastric carcinoma
  • Overall survival
  • SNAIL
  • SNP

Cite this

Zhang, Baozhen ; Zhou, Jing ; Liu, Zhaojun ; Gu, Liankun ; Ji, Jiafu ; Kim, Woo Ho ; Deng, Dajun. / Clinical and biological significance of a − 73A > C variation in the CDH1 promoter of patients with sporadic gastric carcinoma. In: Gastric Cancer. 2018 ; Vol. 21, No. 4. pp. 606-616.
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title = "Clinical and biological significance of a − 73A > C variation in the CDH1 promoter of patients with sporadic gastric carcinoma",
abstract = "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.",
keywords = "Allele-specific repression, CDH1, DNA methylation, Gastric carcinoma, Overall survival, SNAIL, SNP",
author = "Baozhen Zhang and Jing Zhou and Zhaojun Liu and Liankun Gu and Jiafu Ji and Kim, {Woo Ho} and Dajun Deng",
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Clinical and biological significance of a − 73A > C variation in the CDH1 promoter of patients with sporadic gastric carcinoma. / Zhang, Baozhen; Zhou, Jing; Liu, Zhaojun; Gu, Liankun; Ji, Jiafu; Kim, Woo Ho; Deng, Dajun.

In: Gastric Cancer, Vol. 21, No. 4, 01.07.2018, p. 606-616.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Clinical and biological significance of a − 73A > C variation in the CDH1 promoter of patients with sporadic gastric carcinoma

AU - Zhang, Baozhen

AU - Zhou, Jing

AU - Liu, Zhaojun

AU - Gu, Liankun

AU - Ji, Jiafu

AU - Kim, Woo Ho

AU - Deng, Dajun

PY - 2018/7/1

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N2 - 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.

AB - 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.

KW - Allele-specific repression

KW - CDH1

KW - DNA methylation

KW - Gastric carcinoma

KW - Overall survival

KW - SNAIL

KW - SNP

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U2 - 10.1007/s10120-017-0778-6

DO - 10.1007/s10120-017-0778-6

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SN - 1436-3291

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