الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Colorectal cancer is a heterogeneous group of diseases with distinctive genetic and epigenetic background. In order to the improve clinical management and better predict patient outcome, attempts have been made to classify colorectal cancers based on tumor location, histology, etiologic factors, and molecular mechanisms of tumorigenesis.
Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome is now molecularly defined as a cancer-predisposing syndrome secondary to a germline mutation in one of a set of DNA mismatch repair (MMR) genes, (MLH1, MSH2, MSH6, PMS2). Almost 90% of patients have mutations in either MLH1 or MSH2 genes, while mutations in MSH6 and PMS2 genes are much less frequent. Germ line mutations in MSH6 and PMS2 occur in about 10% of families with LS, but a role for germline mutations in MLH3 in LS is still debated. Constitutional MSH6 mutations are more highly associated with distal colorectal cancer, and constitutional mutations of both MSH6 and PMS2 are characterized by reduced penetrance.
The current study is the first to present and analyze data on the prevalence of MMR gene deficiency among CRC patients presenting to the Main University Hospital, Alexandria Faculty of Medicine which represents a referral centre in the city of Alexandria. The aim of study was to assess the prevelance of cases suggestive of HNPCC using immunohistochemistry for 4 MMR genes; MLH1, MSH2, MSH6 and PMS1. Immunohistochemistry was chosen as it is a simple, sensitive, easy to perform, non expensive technique that can verify the MMR gene expression status and specify the defective gene. Immunohistochemistry has been shown to have both high specifity and sensitivity in predicting MSI-status. It can therefore provide gene specific information that can guide further genetic testing. It has several advantages over MSI testing as a first line screening tool to identify HNPCC and is readily available as a routine technique in pathology laboratories, and can be performed on FFPE tissue.
The current study included formalin fixed paraffin embedded (FFPE) specimens of 56 patients who underwent colectomy (total or partial) for colonic adenocarcinoma in the period between June 2012 and December 2015.The specimens were retrieved retrospectively from the archives of the Pathology department. The formalin-fixed paraffin-embedded tissue blocks were cut and stained with Hematoxylin and Eosin (H&E) stain. After examination of all Hematoxylin and eosin (H&E) stained slides of each case the most representive section showing a full thickness of viable tumor tissue and with adjacent non neoplastic colonic mucosa was selected for IHC studies. The corresponding tissue block was retrieved and four 5 microns thick sections from each case were cut and mounted on positively charged, coated slides(polysine, Bio Optica, Milano, Spain) for immunostaining with: MSH2, MSH6, MLH1 and PMS2.
Based on the results of the utilized IHC panel, among the 56 studied CRC cases; 48 cases (85.7%) were MMR proficient and8 cases (14.3%) were mismatch repair deficient. MMR defects due to germ line mutations of MSH2 were the commonest (5 cases, 62.5%). In 3 cases (37.5%) the MSH2 loss was combined with loss of MSH6 expression, while in remaining 3 cases the MSH2 loss was isolated. Loss of PMS2 expression was identified in 2 (25%) of the MMR deficient cases. The least common was the isolated loss of MLH1 (one case, 12.5%).
In the present study, the mean age at diagnosis was 52.88 years. No statistically significant association was observed between patients’ age and MMR deficiency status. Four out of the 8 dMMR cases were female (50%) and four cases were males (50%). There was no statistically significanly relation between patients’ sex and MMR deficiency.