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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-11-22

AUTHORS

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

ABSTRACT

BackgroundCDH1 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).MethodsSGC 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.ResultsKaplan–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.ConclusionThe − 73A > C variation may lead to differences in the overall survival of SGC patients and allele-specific repressions of CDH1. More... »

PAGES

606-616

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10120-017-0778-6

DOI

http://dx.doi.org/10.1007/s10120-017-0778-6

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1092905120

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29168119


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34 schema:description BackgroundCDH1 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).MethodsSGC 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.ResultsKaplan–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.ConclusionThe − 73A > C variation may lead to differences in the overall survival of SGC patients and allele-specific repressions of CDH1.
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41 schema:keywords BackgroundCDH1 germline mutations
42 C patients
43 CDH1
44 CDH1 DNA methylation
45 CDH1 promoter
46 CDH1 promoter activity
47 Chinese cohort
48 ConclusionThe
49 CpG islands
50 DNA methylation
51 Korea cohort
52 MethodsSGC patients
53 PCR
54 PCR analysis
55 PCR sequencing
56 ResultsKaplan–Meier analyses
57 SGC patients
58 activity
59 allele-specific repression
60 alleles
61 analysis
62 assays
63 biological significance
64 bisulfite
65 box
66 cancer cell lines
67 carcinoma
68 cell lines
69 chromatin immunoprecipitation primer extension PCR
70 cohort
71 data
72 differences
73 diffuse gastric carcinoma
74 extension PCR
75 gastric carcinoma
76 gastric tissue
77 genetic variation
78 germline mutations
79 hereditary diffuse gastric carcinoma
80 immunoprecipitation primer extension PCR
81 independent Korea cohort
82 independent cohort
83 influence
84 islands
85 lines
86 methylation
87 mutations
88 overall survival
89 patients
90 polymorphism
91 prevalence
92 primer extension PCR
93 progression
94 promoter
95 promoter activity
96 promoter region
97 ratio
98 ratio of SNAIL
99 recruitment
100 recruitment of SNAIL
101 region
102 reporter assays
103 repression
104 sequencing
105 shore
106 significance
107 snails
108 sporadic gastric carcinomas
109 strong influence
110 survival
111 tissue
112 transcription activity
113 variation
114 vitro
115 vivo
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