Incidence Feature Analysis Of Young Or/and Hereditary Diffused Gastric Cancer And The Effect Of CDH1 Gene Alteration On The Hereditary Diffused Gastric Cancer Kindred

Background: Gastric cancer is one of the leading malignant diseases in China. The gastric cancer seemed more popular in youth within the past a few years. The research aimed to analyze the features of these patients and to compare the difference between the youth and the older patients, the role of hereditary factor was also analyzed in the research. E-cadherin, also known as CAM 120/80, is an important cell-cell adhesion protein fulfilling a prominent role in epithelial differentiation. Down regulation of expression or impaired function of E-cadherin will lead the cells to poor intercellular adhesion through inhabiting homophilic binding. The research investigates the expression pattern in the hereditary diffused gastric cancer and sporadic intestinal gastric cancer. As the methylation of the CpG Island in CDH1 gene promoter was an important factor to gene expression silence, the hypermethylation status was also evaluated in the research. CDH1 gene mutation also plays an important role in the down-regulation of E-cadherin, the somatic mutation had been discovered in many types of carcinoma, as well as the germline mutation in hereditary gastric carcinoma patients andtheir families. Recently, more and more researches reinforce that E-cadherin plays an important role in the differentiation, growth and invasion of HGC. The last part of the research was aimed to explore the novel germline mutation in hereditary gastric cancer kindred.Methods: From March 1988 to April 2003, there was more than 2000 gastric cancer patients were diagnosis in our hospital. The electronic database of these patients was built and the analysis platform was programming by Delphi language of Borland Company (Version 6.0). The incidence and pathology features were analyzed based on the electronic database. The immunohistochemistry SP method was used for evaluated E-cadherin protein expression in the tumor tissues of hereditary diffused gastric cancer and sporadic intestinal gastric cancer. MS-PCR was used to detect the hypermethylation status of CpG Island in CDH1 gene promoter of DNA from these gastric cancer tissues. Twelve hereditary gastric cancer families were selected strictly followed the ICG-HGC and IGCLC Amsterdam criteria. Ninety-five blood specimen and 11 tissuse specimen were collectd for research. The genomic DNA was extracted from the blood or the tissue and 16 exon of CDH1 gene were amplified by PCR. The amplicon was screened by denaturing high performance liquid chromatography, the mutation samples screened by DHPLC was confirmed by DNA directly sequencing.Results: The database was successfully built and total 2109 patients' data was recorded, each record included 38 fields and the field can be used for searching either alone or combination. 1839 patients of 2109 wereconfirmed by pathologic diagnosis, the male was significantly more than female with a ratio 2.80. There were 247 patients whose age of onset less than 45, the female patients equaled roughly to the male patients in these youth. Different from the older gastric cancer patients who had the intestinal gastric cancer; most of these young patients were diffused gastric cancer, and the young patients had a high hereditary background, the male seemed to be affected more than female. Compared with the normal control group, both the sporadic intestinal GC and the hereditary diffused GC had a significantly reduce of E-cadherin expression (p<0. 05), and a statistic higher expression positive rate was also found in the early stage of the sporadic intestinal GC (p<0. 05) but not in the hereditary diffused GC The hypermethylation rate (5/30) of CDH1 promoter in sporadic intestinal GC is significantly lower than that (21/30) in hereditary diffused GC. Analyzed combining with the immumohistochenstry, the result suggested that the hypermethylation is an early onset molecular changes in GC especially in hereditary diffused GC. Five novel germline mutation of CDH1 gene were found in 20 members in 5 of 12 kindred. Two truncate mutations were discovered from 3 members and 3 members from two families respectively. One mutation is CAG-TAG of code 152 in exon 4, the other is TAT-TAG of code 523 in exon 11. Other 4 and 5 members from two families shared the same shift mutation of code 751 in exon 14, AAC-AAG. This mutation will leaded to an aa change, Asn-*Lys, in exon 14. A SNP always accompanied with a mutation just above exon 1 was detected from 5 members of another family. 8 of 20 carriers in these 5 families were morbidity and all of the 8 patients had one of the mutations.