Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability

Citation
Y. Miyakura et al., Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability, GASTROENTY, 121(6), 2001, pp. 1300-1309
Citations number
30
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Gastroenerology and Hepatology","da verificare
Journal title
GASTROENTEROLOGY
ISSN journal
0016-5085 → ACNP
Volume
121
Issue
6
Year of publication
2001
Pages
1300 - 1309
Database
ISI
SICI code
0016-5085(200112)121:6<1300:EMOHPR>2.0.ZU;2-Q
Abstract
Background & Aims: Methylation of the hMLH1 promoter region has been sugges ted to cause microsatellite instability (MSI) in sporadic colorectal carcin oma (CRC). We studied the methylation profile in a wide region of the hMLH1 promoter and compared with the hMLH1 protein expression and MSI status in 88 cases of sporadic CRC. Methods: Na-bisulfite treatment and polymerase ch ain reaction single-strand conformation polymorphism analysis was performed using 5 sets of polymerase chain reaction primers spanning the promoter re gion of the hMLH1 to examine methylation status. Results were compared with immunostaining using anti-MLH1 monoclonal antibody and MSI status of the t umor samples. Results: Methylation status was classified as full or partial methylation. Full methylation indicates the methylation of all CpG sites i n the examined regions. Methylation of the hMLH1 promoter was observed in 8 8.9% (16 of 18) of CRCs showing high frequency MSI (MSI-H), among which 89% (14 of 16) had full methylation with reduced hMLH1 protein expression. All cases showing full methylation were proximal colon tumors with MSI-H. In c ases with partial methylation, only the upstream region of the hMLH1 promot er was methylated. Partial methylation was also shown in 33.3% (6 of 18) of the normal mucosa of MSI-H cases. Frequencies of methylation were signific antly correlated with female gender (P = 0.0009) and aging (P = 0.007). Con clusions: Full methylation of the hMLH1 promoter region and subsequent gene inactivation may play a crucial role in the carcinogenesis of MSI-H CRCs i n the proximal colon. Methylation upstream of the hMLH1 promoter appears to be an early event in the carcinogenesis of MSI-H tumors.