Hypermethylation Of hMLH1 Gene Promoter Research Articles

Effect of methylation of hMLH1 gene promotor on stage tumorigenesis and progression of human gastric cancer

To illustrate the role of methylation level of hMLH1 gene promoter in different stages of gastric carcinogenesis by methylation-specific PCR (MSP) detection of samples from paracancerous tissue and gastric cancer tissue. Methylation status of hMLH1 gene promoter of 40 patients undergoing radical stomach cancer operation in the Tumor Research Institute of China Medical University between January 2006 and August 2006 was detected by MSP. For each patient, 2 samples were chosen from the cancer site, paracancerous tissues of 1 cm, 3 cm, 5 cm away from the cancer site, separately. One sample was used in pathology examination, and the other in methylation detection. Positive rates of hMLH1 gene promoter methylation in the paracancerous tissues of 1 cm, 3 cm, 5 cm away from the cancer site were 10%(4/40), 12.5%(5/40) and 2.5%(1/40) respectively, which were significantly lower than 32.5%(13/40) in cancer site(all P<0.05). Pathological examination showed precancerous lesions in 23 samples of paracancerous 1 cm and 3 cm tissues and normal tissues in 24 samples of paracancerous 5 cm tissues. Positive rates of hMLH1 gene promoter methylation in the cancer site, paracancerous tissue and normal gastric tissue were 32.5%(13/40), 8.7%(2/23) and 0(0/24) (P<0.01). For cancer tissue penetrated the gastric serosa, 8 out of 14 tissue samples were positive methylation (57.1%), which was significantly higher compared with 5 out of 26 tissue samples without penetration of gastric serosa(19.2%). Positive rate of hMLH1 gene promoter methylation in tissue samples with 7 or more of metastatic lymphatic node number was 61.5%(8/13), which was higher compared to that with less than 7(5/27, 18.5%) (P<0.05). No significant differences of positive rate of hMLH1 gene promoter methylation were found between different tumor gross types, tumor grow pattern, tumor differentiation degree, patient age and sex(all P>0.05). Hypermethylation of hMLH1 gene promoter may be associated with the carcinogenesis stages and progression of human gastric cancer.

Head and neck squamous cell carcinoma: mismatch repair immunohistochemistry and promoter hypermethylation of hMLH1 gene

Squamous cell carcinomas of the head and neck are the sixth most frequently occurring cancers and the seventh leading cause of cancer-related deaths worldwide. Epigenetic alteration, using promoter hypermethylation of hMLH1 gene, is important for the development of head and neck squamous cell carcinoma (HNSCC). Aim of this Work The aim of the present study is to analyze the relationship between protein expression and promoter hypermethylation of the hMLH1 gene in HNSCC and correlating inactivation of this gene with clinical parameters. Materials and Methods Paired normal and tumor specimens from 49 patients with HNSCC were collected from Otolaryngology Department, Minia University Hospital, from 2006 to 2009. We analyzed hMLH1 protein expression and promoter hypermethylation by immunohistochemical and methylation-specific polymerase chain reaction (MSP). Results Decreased hMLH1 protein expression and hMLH1 promoter hypermethylation were shown in 15 (30.6%) and 14 (28.6%) cases, respectively. Eleven cases showed dysplasia and or carcinoma in situ in the surface squamous epithelia, and all were positively stained for the hMLH1 protein. hMLH1 promoter hypermethylation was detected in 10 (20.4%) cases of normal-appearing squamous mucosa adjacent to invasive carcinoma. Thirteen (86.7%) of 15 cases that were negative for the hMLH1 protein showed promoter hypermethylation, whereas 33 (97%) of 34 cases positive for the protein were negative of promoter methylation. Promoter hypermethylation was detected in 1 (7.1%) case in which invasive tumor cells were moderately positive for the hMLH1 protein. No significant correlation was observed between hMLH1 protein expression or hMLH1 promoter hypermethylation and any of clinicopathologic parameters. Conclusions hMLH1 gene may be detected early in head and neck squamous carcinogenesis. Promoter hypermethylation is an important mechanism for hMLH1 gene inactivation in HNSCC.

Standardized approach for microsatellite instability detection in gastric carcinomas

Microsatellite instability (MSI) defines a specific type of genetic instability. Although consensus diagnostic criteria for MSI definition in colorectal cancer have been established, their utility in other tumor types remain to be proven. Previously we developed a mathematical model for MSI definition in colorectal cancer. The aim of this study was to establish diagnostic criteria for MSI evaluation in human gastric cancer. We designed an algorithm for the efficient characterization of MSI and used it to analyze data on 7 microsatellite markers in 35 gastric carcinomas. Theoretical models considering 1, 2, or 3 populations were tested against the data collected. Also, hypermethylation of hMLH1 gene promoter and hMLH1 protein expression were studied. The observed frequencies of MSI in our series of samples best fit a 2-population model: stable and unstable, defined by instability in 2 or more of a minimum of 7 markers analyzed. MSI was observed in 29% of the tumors. Misclassification rate was <4% when any 7 loci were analyzed. MSI(+) tumors inversely associated with p53 protein overexpression. A good correlation between hMLH1 status (either protein or promoter hypermethylation) and MSI classification was observed. We have developed a simple, sensitive, and specific approach to assess the presence of MSI in gastric cancer that may have clinical applications.

599 Promoter hypermethylation of hMLH1 gene in liver fluke related cholangiocarcinoma

599 Promoter hypermethylation of hMLH1 gene in liver fluke related cholangiocarcinoma