Background: Patients with a multiple endocrine neoplasia type 1 (MEN1)-associated Zollinger–Ellison syndrome (ZES) show multifocal duodenal gastrinomas and precursor lesions.
Aims: To test these lesions for loss of heterozygosity (LOH) of the MEN1 gene locus on chromosome 11q13, and to investigate 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 hybridisation (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: 28 of a total of 33 duodenal neuroendocrine tumours (NETs) were gastrin-producing tumours; 13/28 (46.4%) revealed LOH on 11q13 and/or C11. Five of the NETs were somatostatin-expressing tumours, two revealing LOH. Allelic loss was detected in tumours as small as 300 μm (gastrin) and 400 μm (somatostatin) in diameter. The gastrin-producing tumours 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 patients with MEN1. The observation of distinct deletion patterns in small synchronous tumours supports the concept that each gastrin-producing tumour in an individual MEN1 patient arises from an independent cell clone.
- C11, centromere 11
- CgA, chromogranin A
- FISH, fluorescence in situ hybridisation
- FITC, fluorescein isothiocyanate
- LOH, loss of heterozygosity
- MEN1, multiple endocrine neoplasia type 1
- NET, neuroendocrine tumour
- SSC, standard sodium citrate
- ZES, Zollinger–Ellison syndrome
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↵* These authors contributed equally to this work.
Published Online First 27 January 2007
Funding: This study was supported by the Hensel Stiftung Kiel (F370011, MA and GK), the Swiss National Foundation (SNF 31-18257, AP and PK) and the German Society of Pathology (MA). Some results of this study are part of NG’s MD thesis. NG and TH have research fellowships sponsored by Ipsen, Ettlingen and the Hensel Stiftung, Kiel, Germany.
Competing interests: None.
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