Aims: Patients with a multiple endocrine neoplasia type 1 (MEN1) associated Zollinger-Ellison syndrome (ZES) show multifocal duodenal gastrinomas and precursor lesions. These lesions were tested for loss of heterozygosity (LOH) of the MEN1 gene locus on chromosome 11q13. In addition, it was investigated whether the MEN1-related endocrine cell changes also involved somatostatin cells.
Material and methods: Tissue specimens from six patients with MEN1 and ZES were analysed by immunohistochemistry and immunofluorescence. LOH analysis was performed by fluorescence in situ hybridization (FISH), using probes containing the MEN1 gene locus and the centromere 11 (C11) region. For simultaneous analysis of hormones and allelic deletions a combined FISH/immunofluorescence protocol was established.
Results: Twenty-eight of a total of 33 duodenal neuroendocrine tumors (NETs) were gastrin-producing tumors; 13/28 (46.4%) revealed LOH on 11q13 and/or C11. Five of the NETs were somatostatin-expressing tumors, two revealing LOH. Allelic loss was detected in tumors as small as 300 μm (gastrin) and 400 μm (somatostatin) in diameter. The multiple gastrin-producing tumors showed different deletion/retention patterns. Hyperplastic somatostatin cell lesions similar to those of the gastrin cells were present in all patients. The hyperplastic lesions of both cell lines consistently retained both 11q13 alleles.
Conclusions: Allelic deletion of the MEN1 gene may reflect a pivotal event in the development of multifocal gastrin and somatostatin cell neoplasms in the duodenum of MEN1 patients. The observation of distinct deletion patterns in very small synchronous tumors supports the concept that each gastrin-producing tumor in an individual MEN1 patient arises from an independent cell clone.
- duodenal gastrinoma
- gastrin cell hyperplasia
- menin gene