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Analysis of inactivation of hMLH1 by promoter hypermethylation and microsatellite instability in gastric carcinogenesis

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Chinese Journal of Clinical Oncology

Abstract

OBJECTIVE To study the microsatellite instability (MSI) and methylation state of the hMLH1 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, hMLH1 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 hMLH1 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 hMLH1 promoter. DNA sequencing and immunohistochemistry results also confirmed that hMLH1 promoter methylation could lead to loss of the hMLH1 protein and gene silence which sequentely resulted in gene mismatch and MSI.

CONCLUSION Accumulation of MSI and hMLH1 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.

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Authors and Affiliations

  1. Basic Medical Research Center of Tianjin Medical University, 300070, Tianjin, China

    Dong Wang, Yao Xu, Xin Geng & Weiming Zhang

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  1. Dong Wang
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  2. Yao Xu
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  3. Xin Geng
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  4. Weiming Zhang
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Correspondence to Dong Wang.

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Wang, D., Xu, Y., Geng, X. et al. Analysis of inactivation of hMLH1 by promoter hypermethylation and microsatellite instability in gastric carcinogenesis. Chin. J. Clin. Oncol. 3, 102–109 (2006). https://doi.org/10.1007/s11805-006-0082-4

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  • DOI: https://doi.org/10.1007/s11805-006-0082-4

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