Survey of genetic alterations in gastrinomas

Gastrinomas are rare gastrin-secreting endocrine tumors that usually arise in the duodenum or pancreas and, if untreated, can cause severe peptic ulce rs or metastatic disease. Although most tumors are sporadic, they are espec ially common in patients with multiple endocrine neoplasia type 1 (MEN1), a nd 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 n ot universal, and it is highly likely that other genetic defects play a sig nificant role. In the present study, an in-depth analysis of the DNA of eig ht tumors was carried out in an effort to localize these areas. The experim ents consisted of an analysis of 400 microsatellite marker loci distributed evenly throughout the human genome, and the results were confirmed with co mparative genomic hybridization, Whereas deletions encompassing the MEN1 ge ne were seen in two tumors, the most striking result was multiple large rea rrangements on chromosome 1 in two of the tumors with hepatic metastases, I n several instances, an individual tumor had abnormalities of every informa tive maker on a given chromosome, presumably as a result of aneuploidy affe cting that chromosome. Such defects were only seen in the four large or agg ressive tumors, and the total number of chromosomes affected in a tumor ran ged from 1 to a high of 13 in a patient who had an unusually aggressive tum or. This tumor also showed microsatellite instability, and this is the firs t report of such a defect in gastrinomas, This study implicates chromosome 1 defects, aneuploidy, and perhaps mismatch repair defects as important fea tures of gastrinomas; deletions involving the MEN1 gene were confirmed, but the rest of the genome was free of large deletions or amplifications.