Lack Of Expression Of HMSH2 Correlated With Methylation Of The HMSH2 Promoter And Apoptosis In Cervical Adenocarcinoma

In the past .adenocarcinoma has represented approximately 5% of cervical cancer cases, with the remainder being predominantly of squamous histology. More recently, however, published data show that adenocarcinoma now constitute approximately 20 ~ 25% of cervical carcinoma. The 5-year survival rates for adenocarcinoma have reported 10~30% lower than for squamous cell carcinoma at every FIGO stage, thus cervical adenocarcinoma is an important and increasing health problem, and a better understanding of the molecule events involved in the development of this tumour might help to improve the prognosis.Mismatch repair deficiency is linked predominantly to cancers of the colon, endometrium and ovary. Germline alteration of any one of the human MMR genes, MSH2, MSH3, MLH1, MSH6, PMS2 and PMS1, gives rise to hereditary nonpolyposis colon cancer (HNPCC). Predisposed individuals from HNPCC families have a high lifetime risk of developing colorectal carcinoma (70 - 85%), endometrial carcinoma(50%),as well as certain other cancers (below 15%), collectively referred to as the "HNPCC tumor spectrum" . Germline mutations in MSH2 and MLHI are responsible for most HNPCC families.Tumors from HNPCC patients show acquired variation in the number of short tandem repeat units contained within microsatellite sequences (MSI, microsatellite instability). This abnormality results from a failure to correct errors arising in theserepeats during DNA replication, and occurs in approximately 15% of sporadic tumors from the colorectum and other organs as well. Mutation rates in tumor cells with MMR deficiency are 100 - 1000 fold as compared to normal cells. Interestingly, the mechanisms of biallclic inactivation of MMR genes and consequent MSI are different in HNPCC and sporadic tumors. In HNPCC, MMR gene inactivation typically results from a germ line mutation of one allele (first hit) and loss of heterozygosity or somatic mutation of the other allele (second hit). In contrast, an epigenetic mechanism accounts for a majority of sporadic tumors with MMR deficiency, consisting of promoter hypermethylation of a single MMR gene, MLH1. The recent discovery that the MMR system plays an important role also in signalling the presence of DNA damage to the apoptotic machinery implies that the function of MMR gene in cancer may go beyond the mutator phenotype and MSI. There are two classical way involved in apoptosis: one is Fas or TNFR pathway.another is bcl-2 family protein modulating way. Bag-1 and bak are newly cloned apoptotic modulation gene associate with bcl-2 family, particularly BAG-1 may reaction with bcl-2 as well as hepatic growth factor receptor and estrogen receptor and so on to induce apoptosis.Facing the increasing cervical adenocarcinoma, there is an urgency and necessary to study it. We applied immunohisochemistry ,PCR, methylation specific PCR to explore the hMSH2, Fas, FASL, BAG-1 ,bak, Ki67 expression, microsattlite instablity, methylation state of hMSH2 and hMLHl promoter.Part One Relationship between apoptosis and Expression of Mismatch Repair GenehMSHl in Human adenocarcinoma of cervixMaterials Forty-three cervical adenocarcinoma graded FIGO I~1I. were operated in Women 's Hospital of Zhejiang University from January 1990 to August 2000. Thirty-sixIS 7cases were enrolled in this research. According to hisological type, 24 were mucoid adenocarcinoma, 6 adeno-squamous carcinoma, 2 endometriod adenocarcinoma, 2 adenoacanthoma, 2 clear-cell carcinoma. According to differentiation, 9 cases are well differentiation, 15 moderate differentiation, 12 poor differentiation. According to stage, 6 cases are stage I., 16 stage Ib,14 stage II.. All cases had no radiation or chemotherapy before operation.Methods Both carcinoma tissues and their surrounding tissues from 36 patients with adenocarcinoma of cervix were studied for the expression of hMSH2 and Ki67 by immunohistochemical staining and DNA fragment of apoptosis...