|Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1997: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1996: ¥1,600,000 (Direct Cost: ¥1,600,000)
Many genetic alterations in germ line and in somatic tissues have been identified in some gastrointestinal cancers. These alterations include activating mutations in proto-oncogenes, inactivation of tumor supressor genes, and general disturbances of the genome such as changes in ploidy, alterations in DNA methylation, and genetic instability. The specific genetic changes that occur in gastrointestinal tumours have been well chronicled elsewhere, but it is not clear which of these changes may be responsible for specific pathological stages of disease progression in individual tumors. We hypothesized that visually identifiable pathological distinctions in neoplastic lesions of the gastrointestine are all based on genetic difference, but reasoned that one would be required to sample multiple, well-defined cellular populations microdissected from individual tumors that exhibited more than one neoplastic stage to determine which genetic events were likely to be responsible for progression.
To accomplish this, we removed multiple pathologically defined speciments from individual slides, extracted the DNA from each peace, and performed polymerase chain reaction based microsatellite assays to detect loss of heterozygosity (LOH) within or near the adenomatous polyposis coli (APC), p53, deleted in colorectal cancer (DCC) genes on chromosomes 5q, 17p and 18q, respectively and microsatelliteinstability (MSI) to indicate replication error (RER).
Microalleolotyping has permitted us to detect LOH and MSI events in tiny, pathologically defined foci of gastrointestinal neoplasia. In colorectal neoplasia, we have found apparent genomic stability in adenoma with low-grade dysplasia and invasive cancers. Chaotic alleic losses occur in high-grade dysplasia, thelesion that marks the transition from benign to malignant neoplasia in the colon, which was associated with LOH at 17p. In stomach cancer, alleic losses occurfrequently mainly in well differentiated adenocarcinomas as found as colorectal carcinomas, meanwhile MSls were frequently shown in poorly differentiated adenocarcinomas. LOHs occur frequently in gallbaldder carcinomas, on the other hand MSls occur frequently in bile duct carcinomas.
Microalleolotyping has permitted a clarification in individual gastrointestinal neoplasias. Less