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Title: Molecular mechanisms of E-cadherin inactivation in hereditary diffuse gastric cancer
Author: Barber, M.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2008
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Abstract:
In this study three mechanisms (somatic mutation, promoter hypermethylation and loss of heterozygosity) of inactivation of the second allele of the E-cadherin gene were investigated in paraffin embedded tumour material from 18 HDGC patients with germline E-cadherin mutations. Somatic mutations, both exonic (two patients) and intronic (three patients), and promoter methylation (four patients) were identified. Furthermore, it was possible to demonstrate that in two of these patients methylation occurred specifically on the allele which was not affected by germline mutation. Loss of heterozygosity was not identified in any patient. Somatic mutation and promoter methylation of the E-cadherin gene were also analysed in archival tumour material from patients within HDGC families without germline E-cadherin mutations. Neither inactivation mechanism was detected in this group of patients. E-cadherin expression was investigated at both the mRNA and protein levels in HDGC patients with and without germline E-cadherin mutations. Expression was abnormal or absent in most cases and this was evident at the transcriptional level. N-cadherin protein was not expressed in any analysable tumour material. Immunohistochemical analysis of prophylactic gastrectomy specimens from HDGC patients with germline E-cadherin mutations demonstrated that E-cadherin expression was reduced or absent in all of the microscopic cancerous foci analysed. Abnormal E-cadherin expression was confined to the cancerous cells and this may help pathologists identify these lesions more rapidly. To further investigate the phenotype of the signet ring cells within these lesions markers of proliferation (Ki-67) and epithelial-mesenchymal transition (vimentin and cytokeratins 8 and 18) were investigated. Results from this analysis suggest that these cells are not highly proliferative and that they have expression patterns characteristic of epithelial cells. Therefore it is likely that these lesions represent an early, indolent stage of HDGC development. The position of the foci within the prophylactic gastrectomy specimens were systematically analysed and a prediction for the upper third of the stomach was identified. This suggests that targeted endoscopic biopsy taking may improve the surveillance outcomes for these patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.596343  DOI: Not available
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