Association between cyclin D1 polymorphism with CpG island promoter methylation status of tumor suppressor genes in gastric cancer.
BACKGROUND
CpG island hypermethylation of tumor suppressor genes is highly involved in gastric carcinogenesis, and enhanced cell proliferation could accelerate this process. Cyclin D1 regulates cell cycle function and may play a role in methylation-related carcinogenesis.


OBJECTIVE
We investigated the association between Cyclin D1 gene G870A polymorphism and the methylation status of tumor suppressor genes in gastric cancer.


METHODS
Polymorphisms at G870A in the Cyclin D1 gene were genotyped, and methylation status of the p14, p16, DAP-kinase, and CDH1 genes were determined by methylation-specific-polymerase chain reaction in 139 gastric cancer tissues. CIHM high was defined as three or more methylated CpG islands.


RESULTS
Although no association was found between methylation status and different stages and Lauren's subtypes, patients with CIHM of DAP-kinase showed significantly worse survival than those without (p = 0.017). In addition, the number of methylated sites was also associated with survival curves (p = 0.0397). The 870G carrier a significantly lower prevalence of CIHM high compared to the AA genotype in advanced-stage gastric cancer (adjusted OR = 0.32, p = 0.047). A weak correlation between the same genotypes and CIHM of p14 were found in the same subtype (adjusted OR = 0.32, p = 0.052). The mean methylation number was significantly lower in G carriers than in AA genotypes in advanced-stage gastric cancer (p = 0.017).


CONCLUSIONS
Genetic polymorphism of CCND1 is associated with CIHM status in gastric cancer, especially in the advanced stage, but is independent of clinico-pathological features.
Tahara
Tomomitsu
T
Department of Gastroenterology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake, Aichi 470-1192, Japan. tomomiccyu@yahoo.co.jp
Shibata
Tomoyuki
T
Nakamura
Masakatsu
M
Yamashita
Hiromi
H
Yoshioka
Daisuke
D
Okubo
Masaaki
M
Yonemura
Joh
J
Maeda
Yoshiteru
Y
Maruyama
Naoko
N
Kamano
Toshiaki
T
Kamiya
Yoshio
Y
Fujita
Hiroshi
H
Nakagawa
Yoshihito
Y
Nagasaka
Mitsuo
M
Iwata
Masami
M
Hirata
Ichiro
I
Arisawa
Tomiyasu
T
D000368:Aged; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D019940:Genes, bcl-1 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
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