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An investigation of genetic alterations in gastric and colorectal cancer

Sud, Richa; (1998) An investigation of genetic alterations in gastric and colorectal cancer. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The widely accepted model of colorectal tumourigenesis involves an accumulation of mutations in tumour suppressor genes and oncogenes which include the APC (Adenomatous Polyposis Coli) gene, the p53 gene, a gene on chromosome 18q, and the K-ras gene. In addition, replication error (RER) at short repeat sequences is observed in a subset of colorectal tumours and has been associated with a defect in the DNA mismatch repair system. In contrast, the genetic alterations that are most significant in the development and progression of gastric (stomach) cancer are unknown. In this study, twenty-six gastric carcinoma and corresponding normal tissues were investigated for alterations of the APC, MCC (Mutated in Colorectal Cancer), DCC (Deleted in Colon Carcinoma), p53, and hMSH2 (human MutS homologue 2) genes, and for replication error (RER) and loss of heterozygosity (LOH) at twelve microsatellite repeat loci. Some of the genetic alterations were viewed in comparison with colorectal cancer. Forty-three colorectal carcinoma and corresponding normal tissues were investigated for alterations of the APC and hMSH2 genes, and for RER and LOH at at twelve microsatellite repeat loci. Somatic mutations of the APC gene were observed infrequently in gastric carcinomas (4% of tumours). In addition, infrequent LOH was observed at the APC, MCC, and DCC loci, in 8%, 10%, and 5% informative cases respectively. Alterations of the p53 gene were more frequent: somatic p53 mutations were detected in 31% of gastric carcinomas while LOH at the p53 locus was observed in 37.5% of informative cases. RER was detected in 11.5% of gastric carcinomas, at one or more microsatellite repeat loci. Of the 12 microsatellite repeat loci, LOH was most frequently observed in gastric carcinomas at D22S351 (30% informative cases) suggesting that a tumour suppressor gene on chromosome 22q may be important in gastric tumourigenesis. During mutational analysis of the hMSH2 gene, an intronic 4 base pair insertion at 31 base pairs upstream of the beginning of exon 13 was detected in both tumour and normal tissue from one gastric carcinoma case. Additionally, a T to C transition polymorphism was detected at the -6 position of the splice acceptor site of hMSH2 exon 13, and characterized in the 26 gastric carcinoma cases, 43 colorectal carcinoma cases, and 50 unaffected unrelated individuals. Somatic mutations of the APC gene were observed in 37.2% of colorectal carcinomas. In 3 tumours, two independent somatic APC mutations were observed. LOH at APC was observed in 24.3% of informative colorectal tumours. RER was detected in 14% of colorectal carcinomas, at one or more loci. Of the microsatellite repeat loci, LOH was most frequently observed in colorectal carcinomas at p53CA (58.1% informative cases) and at D18S61 (33.3% informative cases). This study confirms the importance of alterations of the APC gene and RER in colorectal tumourigenesis. The results are not supportive of a common molecular pathogenesis for colorectal and gastric cancer, not even for the intestinal histological type of gastric cancer. Tumour suppressor genes other than those investigated in the present study must play a more important role in gastric tumourigenesis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: An investigation of genetic alterations in gastric and colorectal cancer
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences; Colorectal cancer; Gastric cancer
URI: https://discovery.ucl.ac.uk/id/eprint/10104191
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