Aims: The identification of precursor lesions has a great impact on our understanding of tumorigenesis. In this study we investigated whether preneoplastic lesions can be identified in sporadic gastrinomas and in gastrinomas in multiple endocrine neoplasia type 1 (MEN1) patients. These lesions were tested for loss of heterozygosity (LOH) of the MEN1 gene locus on chromosome 11q13.
Material and methods: Tissue specimens from 25 patients with Zollinger-Ellison syndrome (ZES) were analyzed. The MEN1 status was assessed clinically and by mutational analysis. For simultaneous analysis of hormones and allelic deletions a combined FISH fluorescence in situ hybridization/immunofluorescence protocol was established.
Results: Hyperplastic gastrin cell lesions were present in the nontumorous mucosa of all MEN1 patients, but not in 12 patients with sporadic duodenal gastrinomas. The hyperplastic gastrin cells retained both 11q13 alleles. 11q13 LOH was, however, detected in duodenal gastrinomas, some as small as 300 microm in diameter, in 13 patients with MEN1.
Conclusions: MEN1-associated duodenal gastrinomas, but not sporadic gastrinomas, are associated with gastrin cell hyperplasia. It is therefore likely that hyperplastic gastrin cell lesions precede the development of MEN1-associated duodenal gastrinomas. Allelic deletion of the MEN1 gene locus may reflect a decisive initial event in the development of multifocal MEN1-associated gastrinomas from hyperplastic gastrin cell lesions.