RT Journal Article
SR Electronic
T1 Analysis of Inactivation of hMLH1 by Promoter Hypermethylation and Microsatellite Instability in Gastric Carcinogenesis
JF Chinese Journal of Clinical Oncology
JO Cancer Biol Med
FD China Anti-Cancer Association
SP 102
OP 109
VO 3
IS 2
A1 Wang, Dong
A1 Xu, Yao
A1 Geng, Xin
A1 Zhang, Weiming
YR 2006
UL http://www.cancerbiomed.org/content/3/2/102.abstract
AB OBJECTIVE To study the microsatellite instability (MSI) and methylation state of the hMLHI gene promoter and their mechanisms underlying the development of gastric cancer.METHODS Forty-one gastric cancer samples were obtained from patients undergoing surgery and 46 chronic atrophic gastritis tissues with dysplasia or intestinal metaplasia (IM) were obtained from patients undergoing gastro-endoscopy. Fourteen normal gastric mucosal samples were used as controls. Genomic DNA was extracted from the samples and 5 microsatellite markers were used to measure MSI. Methylation - specific PCR (MSP) was used to screen the methylation state of the samples. DNA sequencing and immunohistochemistry were performed to verify the results.RESULTS MSI was identified in 22 out of the 41 (53.7%) gastric cancers, of which 8 cases showed high-level MSI (2 or more loci altered) and 14 showed low-level MSI (1 locus altered). MSI was also detected in 12 out of 46 (26.1%) pre-cancerous lesions of the stomach, whereas it was not seen in the normal tissue. Moreover, hMLHI hypermethylation was detected in 17 out of the 41 (41.5%) gastric cancers, 9 out of the 46 (19.6%) pre-cancerous lesions and 0 out of the 14 normal tissue. Significant differences in frequency of MSI and hMLHI promoter methylation were observed among gastric cancers, precancerous lesions and normal gastric tissue. Gastric samples with MSI had a tendency to be hypermethylated in the hMLHI promoter. DNA sequencing and immunohistochemistry results also confirmed that hMLHI promoter methylation could lead to loss of the hMLHI protein and gene silence which sequentely resulted in gene mismatch and MSI.CONCLUSION Accumulation of MSI and hMLHI promoter methylation may be important early molecular events during gastric carcinogenesis and may contribute to the acquisition of a transformed cell phenotype and the development of gastric cancer.