Methylation of GATA-4 and GATA-5 and development of sporadic gastric carcinomas.
OBJECTIVE
To understand the implication of GATA-4 and GATA-5 methylation in gastric carcinogenesis.


METHODS
Methylation status of GATA-4 and GATA-5 CpG islands in human gastric mucosa samples, including normal gastric biopsies from 45 outpatients, gastric dysplasia [low-grade gastric intraepithelial neoplasia (GIN), n = 30; indefinite, n = 77], and 80 paired sporadic gastric carcinomas (SGC) as well as the adjacent non-neoplastic gastric tissues was analyzed by methylation specific polymerase chain reaction (MSP) and confirmed by denatured high performance liquid chromatography (DHPLC). Immunohistochemical staining was used to detect protein expression. The correlation between GATA-4 and GATA-5 methylation and clinicopathological characteristics of patients including Helicobacter pylori (H. pylori) infection was analyzed.


RESULTS
GATA-4 and GATA-5 methylation was frequently observed in SGCs (53.8% and 61.3%, respectively) and their corresponding normal tissues (41.3% and 46.3%) by MSP. The result of MSP was consistent with that of DHPLC. Loss of both GATA-4 and GATA-5 proteins was associated with their methylation in SGCs (P = 0.01). Moreover, a high frequency of GATA-4 and GATA-5 methylation was found in both gastric low-grade GIN (57.1% and 69.0%) and indefinite for dysplasia (42.9% and 46.7%), respectively. However, GATA-4 and GATA-5 methylation was detected only in 4/32 (12.5%) and 3/39 (7.7%) of normal gastric biopsies. GATA-4 methylation in both normal gastric mucosa and low-grade GIN was also significantly associated with H. pylori infection (P = 0.023 and 0.027, two-sides).


CONCLUSIONS
Epigenetic inactivation of GATA-4 (and GATA-5) by methylation of CpG islands is an early frequent event during gastric carcinogenesis and is significantly correlated with H. pylori infection.
Wen
Xian-Zi
XZ
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Etiology, Peking University School of Oncology and Beijing Cancer Hospital & Institute, Fucheng Road No. 52, Haidian District, Beijing 100142, China.
Akiyama
Yoshimitsu
Y
Pan
Kai-Feng
KF
Liu
Zhao-Jun
ZJ
Lu
Zhe-Ming
ZM
Zhou
Jing
J
Gu
Lian-Kun
LK
Dong
Cai-Xuan
CX
Zhu
Bu-Dong
BD
Ji
Jia-Fu
JF
You
Wei-Cheng
WC
Deng
Da-Jun
DJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D050992:GATA5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D016481:Helicobacter Infections / Q000150:complications; D016480:Helicobacter pylori; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology
D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D050992:GATA5 Transcription Factor; C494755:GATA5 protein, human