Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions.
BACKGROUND
Patients with a multiple endocrine neoplasia type 1 (MEN1)-associated Zollinger-Ellison syndrome (ZES) show multifocal duodenal gastrinomas and precursor lesions.


OBJECTIVE
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.


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 microm (gastrin) and 400 microm (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.
Anlauf
M
M
Department of Pathology W, University of Kiel, Michaelisstr 11, 24105 Kiel, Germany. manlauf@path.uni-kiel.de
Perren
A
A
Henopp
T
T
Rudolf
T
T
Garbrecht
N
N
Schmitt
A
A
Raffel
A
A
Gimm
O
O
Weihe
E
E
Knoefel
W T
WT
Dralle
H
H
Heitz
Ph U
PU
Komminoth
P
P
Klöppel
G
G
D000328:Adult; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004379:Duodenal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015408:Gastrinoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics* / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015043:Zollinger-Ellison Syndrome / Q000235:genetics / Q000473:pathology
C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins