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Survey of Genetic Alterations in Gastrinomas

Digestive Diseases [F. Y., R. T. J.] and Genetics and Biochemistry Branches [Y-L. Z., A. M. H., L. J. F.], National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892; Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20892 [I. A. L.]; and Laboratory of Cancer Genetics, University and University Hospital of Tampere, FIN-33101 Tampere, Finland [E. H. M.]

Gastrinomas are rare gastrin-secreting endocrine tumors that usually arise in the duodenum or pancreas and, if untreated, can cause severe peptic ulcers or metastatic disease. Although most tumors are sporadic, they are especially common in patients with multiple endocrine neoplasia type 1 (MEN1), and most studies of these tumors have focused on the role of the MEN1 gene. Although the gene is commonly altered in sporadic tumors, this finding is not universal, and it is highly likely that other genetic defects play a significant role. In the present study, an in-depth analysis of the DNA of eight tumors was carried out in an effort to localize these areas. The experiments consisted of an analysis of 400 microsatellite marker loci distributed evenly throughout the human genome, and the results were confirmed with comparative genomic hybridization. Whereas deletions encompassing the MEN1 gene were seen in two tumors, the most striking result was multiple large rearrangements on chromosome 1 in two of the tumors with hepatic metastases. In several instances, an individual tumor had abnormalities of every informative maker on a given chromosome, presumably as a result of aneuploidy affecting that chromosome. Such defects were only seen in the four large or aggressive tumors, and the total number of chromosomes affected in a tumor ranged from 1 to a high of 13 in a patient who had an unusually aggressive tumor. This tumor also showed microsatellite instability, and this is the first report of such a defect in gastrinomas. This study implicates chromosome 1 defects, aneuploidy, and perhaps mismatch repair defects as important features of gastrinomas; deletions involving the MEN1 gene were confirmed, but the rest of the genome was free of large deletions or amplifications.

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