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(American Journal of Pathology. 1999;154:429-436.)
© 1999 American Society for Investigative Pathology

Regular Articles

Mutations and Allelic Deletions of the MEN1 Gene Are Associated with a Subset of Sporadic Endocrine Pancreatic and Neuroendocrine Tumors and Not Restricted to Foregut Neoplasms

Birgit Görtz* , Jürgen Roth , Akiko Krähenmann* , Ronald R. de Krijger , Seraina Muletta-Feurer* , Katrin Rütimann* , Parvin Saremaslani* , Ernst J. M. Speel* , Philipp U. Heitz* and Paul Komminoth*

From the Department of Pathology* and the Division of Cell and Molecular Pathology, University of Zurich, Zurich, Switzerland, and the Department of Pathology, Erasmus University of Rotterdam, Rotterdam, The Netherlands

	Abstract

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Endocrine pancreatic tumors (EPT) and neuroendocrine tumors (NET) occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). We analyzed the frequency of allelic deletions and mutations of the recently identified MEN1 gene in 53 sporadic tumors including 30 EPT and 23 NET (carcinoids) of different locations and types. Allelic deletion of the MEN1 locus was identified in 18/49 (36.7%) tumors (13/30, 43.3% in EPT and 5/19, 26.3% in NET) and mutations of the MEN1 gene were present in 8/52 (15.3%) tumors (4/30 (13.3%) EPT and 4/22 (18.1%) NET). The somatic mutations were clustered in the 5' region of the coding sequence and most frequently encompassed missense mutations. All tumors with mutations exhibited a loss of the other allele and a wild-type sequence of the MEN1 gene in nontumorous DNA. In one additional patient with a NET of the lung and no clinical signs or history of MEN1, a 5178–9GA splice donor site mutation in intron 4 was identified in both the tumor and blood DNA, indicating the presence of a thus far unknown MEN1 syndrome. In most tumor groups the frequency of allelic deletions at 11q13 was 2 to 3 times higher than the frequency of identified MEN1 gene mutations. Some tumor types, including rare forms of EPT and NET of the duodenum and small intestine, exhibited mutations more frequently than other types. Furthermore, somatic mutations were not restricted to foregut tumors but were also detectable in a midgut tumor (15.2% versus 16.6%). Our data indicate that somatic MEN1 gene mutations contribute to a subset of sporadic EPT and NET, including midgut tumors. Because the frequency of mutations varies significantly among the investigated tumor subgroups and allelic deletions are 2 to 3 times more frequently observed, factors other than MEN1 gene inactivation, including other tumor-suppressor genes on 11q13, may also be involved in the tumorigenesis of these neoplasms.

	Introduction

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The vast majority of NET and EPT occur sporadically, but a subset of tumors is associated with inherited syndromes such as multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau syndrome.^5,6 Although the molecular basis of these familial tumors has recently been established,^5,6 only little is known about the oncogenesis and molecular basis of progression of sporadically occurring EPT and NET.

MEN1 is an autosomal-dominant genetic disorder characterized by the development of NET in the parathyroid glands, the endocrine pancreas or duodenum, and in the anterior pituitary.⁷ Up to 9% of MEN1 gene carriers develop NET at other locations, especially in the foregut (thymus, lung, or stomach), and may also suffer from nonneuroendocrine neoplasms such as lipomas, angiofibromas, or ependymomas.⁷ The gene for MEN1 has previously been localized to chromosome 11q13⁸ and was recently cloned.⁵ A tumor suppressor function for the MEN1 gene has been suggested based on frequent chromosome 11q13 loss of heterozygosity (LOH) in neoplasms of affected patients.^8,9 Allelic deletions^10,11 and recent mutation analysis studies^12-15 had implicated the MEN1 gene as a tumor suppressor in a significant fraction of the sporadic counterparts of typical MEN1 neoplasms and it has been hypothesized that these tumors are restricted to the foregut.^16,17 However, in previous studies Jakobovitz et al¹¹ demonstrated that loss of 11q13 is also encountered in 100% and 63% of sporadic NET of the midgut and hindgut, respectively, suggesting that somatic mutations of the MEN1 gene might also contribute to the pathogenesis of these tumors. A systematic examination of both allelic deletions and mutations of the MEN1 gene in the latter tumor types, however, is missing.

In the present study, we analyzed 53 tumor tissues, including sporadic NET of the lung and gastrointestinal tract and EPT, for inactivation of the MEN1 gene to test the hypothesis that MEN1 gene mutations in sporadic tumors are restricted to foregut tumors. Both allelic deletions of chromosome 11q13 and MEN1 gene mutations were assessed.

	Materials and Methods

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Patient Samples

Frozen tissue samples from 53 patients with EPT or NET were obtained from the files of the Departments of Pathology at the University of Zürich and Erasmus University of Rotterdam. The samples included 30 EPT (9 insulinomas, 5 VIPomas, 3 gastrinomas, 1 glucagonomas, 1 somatostatinoma, 11 nonfunctional tumors) and 23 well differentiated NET (12 lung, 2 stomach, 3 duodenum, 3 ileum, 1 colon, 1 liver, 1 metastasis) (Table 1) . Because a different pathogenic mechanism has been suggested for poorly differentiated (eg, small cell and large cell) neuroendocrine carcinomas, these neoplasms were not included in the present study.

MEN1 Gene Mutation Analysis

Genomic DNA was isolated as recently described.^19,20 DNA from peripheral blood leukocytes of healthy persons served as negative controls and from MEN1 patients from our files as positive controls. The 2790-bp coding region and splice sites of the MEN1 gene were screened for mutations according to our previously published protocols.²¹ Polymerase chain reaction (PCR) fragments ranging from 244 to 409 bp in length were amplified from 100-ng tumor or germline DNA using previously published primers and conditions²¹ (see Table 2 ). In brief, PCR amplification of exons 3 to 9 was performed in a total amount of 50 µl reaction mixture containing 0.2 mmol/L dATP, dTTP, dGTP, dCTP, 50 pmol of each sense and antisense primer, 1.5 mmol/L Mg²⁺, 10 mmol/L Tris-HCl, 50 mmol/L KCl, and 1 Unit Taq DNA polymerase (AmpliTaq Gold, Perkin Elmer, Norwalk, CT). For PCR amplification of exons 2 and 10, Expand High Fidelity DNA Polymerase (Boehringer Mannheim, Mannheim, Germany) and 10% DMSO were used.

MEN1 Allelic Deletion Analysis

Fluorescent in situ hybridization (FISH) analysis was performed as recently described, using the cosmid clone c10B11 (40 kb) containing the MEN1 gene as a probe.²¹ In brief, touch preparations from frozen tissue samples were fixed in 70% ethanol for 1 hour, treated with 100 µg/ml pepsin (Sigma, St. Louis, MO) in 0.01 N HCl for 20 minutes at 37°C, and postfixed for 10 minutes in 1% formaldehyde in phosphate-buffered saline at room temperature.²⁴ Fluorescein-labeled cosmid probe (250 ng) and 20 ng of rhodamin-labeled -repetitive DNA specific for chromosome 11 in hybridization buffer (50% formamide, 10% dextran sulfate, 2x SSC, herring sperm DNA, yeast tRNA, Cot-1 fraction of human DNA) were hybridized overnight in a humidified chamber at 37°C. Posthybridization washes were performed at 45°C in 50% formamide/2x SSC (3 times for 5 minutes) and 0.1x SSC (3 times for 5 minutes). Amplification of the cosmid probe signal was achieved using rabbit anti-fluorescein (Dako, Copenhagen, Denmark) and swine anti-rabbit Ig fluorescein antibodies, followed by dehydration of the slides and mounting in Vectashield (Vector, Burlingame, CA) containing 0.5 µg/ml 4',6-diamidino-2-phenylindole antifade (DAPI, Sigma) for nuclear counterstaining. Hybridization signals of at least 100 interphases for each tumor were scored using a Zeiss Axioplan fluorescence microscope with appropriate filter sets. Images were taken with a CCD camera using the Vysis Quips FISH software (IG Instrumenten-Gesellschaft AG, Bern, Switzerland). The presence of only one MEN1 cosmid signal in more than 30% of tumor cells was interpreted as an allelic deletion. Normal connective tissue in the vicinity of tumors served as internal control and exhibited nuclei with one MEN1 signal in 3 to 7% of cells.

In 34 patients from whom DNA of nontumorous tissue or blood was available, samples were also screened for allelic deletion using three polymorphic markers on 11q13 as recently described²⁵ and the DNA was visualized by silver staining as described above. The markers included an intragenic microsatellite marker (D11S4946) at the MEN1 5' region and two flanking 11q13 markers, PYGM (human muscle glycogen phosphorylase) and D11S4936.²⁶

	Results

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Results of the MEN1 gene mutation and LOH analyses are listed in Tables 3–5 and representative examples are illustrated in Figure 1 .

View larger version (80K): [in this window] [in a new window]   Figure 1. Loss of heterozygosity analysis, PCR-SSCP analysis, and sequence analysis of the MEN1 gene in a sporadic neuroendocrine tumor of the lung (Cd1). Note that only one of the MEN1 genes (green spots, arrows) is detectable in the majority of tumor cells when compared with the chromosomes 11 (red dots) and that one allele of the three 11q13 markers is lost in the tumor DNA (T) when compared to normal tissue (N). The PCR-SSCP of exon 3 shows a band shift (line 4, red arrowheads) in the tumor DNA caused by a D172V missense mutation. In the sporadic endocrine pancreatic tumor P149 the LOH-FISH analysis shows only one signal of chromosome 11 (red) and the MEN1 locus (green), indicating the loss of one chromosome 11 in the majority of tumor cells. PCR-SSCP analysis reveals a band shift in exon 2 (line 3, red arrowheads) caused by an A50F missense mutation.

PCR-LOH and FISH analysis performed in 49 sporadic tumors (PCR-LOH in 8, FISH in 16, and both analyses in 25 tumors) revealed an allelic deletion of the MEN1 locus in 18 tumors (36.7%) and at 11q13 in 19 tumors (38.7%). This additional tumor exhibited an isolated allelic deletion of the PYGM locus. The frequency in EPT was 43.3% (13/30) and in NET 26.3% (5/19). Thus a two- to threefold higher frequency of allelic deletions in comparison to detected MEN1 gene mutations was found in all analyzed tumor groups.

Among the different pancreatic tumor groups, the frequencies of allelic deletions and mutations in insulinomas were 4/9 and 1/9, in gastrinomas 2/3 and 0/3, in VIPomas 4/5 and 2/5, in glucagonomas 0/1 and 0/1, in somatostatinomas 1/1 and 1/1, and in nonfunctioning EPT 3/11 and 0/11. Thus the combined frequency of allelic deletions and mutations in EPT of our series were 13/30 (43.3%) and 4/30 (13.3%), respectively.

In the analyzed sporadic NET, allelic deletions and mutations occurred in 7/19 (26.3%) and 4/22 (18.1%) samples, respectively (lung 2/10 and 2/11, stomach 2/2 and 0/2, duodenal gastrinomas 2/3 and 1/3, small intestine 0/2 and 1/3, colon 0/1 and 0/1, liver 0/1 and 0/1, and metastasis of a gastrointestinal NET 0/0 and 0/1).

Allelic deletions and mutations were found in 18/45 (40%) and 7/46 (15.2%) of foregut tumors and in 0/4 and 1/6 (16.6%) of midgut and hindgut tumors.

	Discussion

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The results of the present study on allelic deletions and mutations of the MEN1 gene imply a role for the MEN1 gene in the development of 15.3% of sporadic EPT and NET. Few studies have been published in which sporadic EPT were investigated for mutations of the MEN1 gene.^14,17,28,29 Collectively, the previously published and present results on a total of 61 EPT indicate that the frequency of allelic deletions of the MEN1 gene in these tumors is 51% (25/49) and the mutation rate is 20.9% (13/62). Among subtypes of EPT, the highest mutation frequencies are encountered in the rare types of EPT⁴ such as VIPomas, somatostatinomas and glucagonomas. The more frequently encountered insulinomas, nonfunctioning EPT, and gastrinomas generally exhibit a lower frequency rate of somatic MEN1 gene mutations, indicating that the molecular mechanisms of the latter tumors might be different from those of the former.

So far, only one study of NET of the gastrointestinal tract and one of NET of the lung have been published.^12,17 Present and recently published data suggest that the overall frequency of allelic deletion at the MEN1 locus in these tumors appears to be 58.4% (31/53) and the mutation rate 23.2% (17/73). Thus, the rates of allelic deletion and mutations of the MEN1 gene in sporadic EPT and NET appear to be very similar, indicating that the MEN1 gene plays a role in the tumorigenesis of approximately one fifth of the sporadically encountered tumors. The highest frequencies of MEN1 mutations in sporadic NET were encountered in the duodenum (31%) and the lung (27%), whereas tumors of the stomach, small intestine, and colorectum exhibit mutations less frequently. These findings indicate that, like tumors of the endocrine pancreas, an organ- or cell type-specific pattern of MEN1 gene mutations might exist. However, this assumption may be biased by the small numbers of tumors examined for certain tumor types.

Combining our results with those recently published, it appears that virtually all examined tumor groups exhibit an overall LOH rate of 50% at the MEN1 locus and that the frequencies of encountered allelic deletions is usually 2 to 3 times higher than the frequency of mutations of the MEN1 gene. This suggests that LOH at 11q13 per se is not an indicator of MEN1 mutations. Such findings can easily be explained by other modes of MEN1 gene inactivation, such as methylation of the promotor or noncoding regions or the presence of mutations in unexamined gene regions. It seems also likely that the higher frequency of allelic deletions is an indicator for the inactivation of yet another tumor suppressor gene on 11q13 in these tumors. Thus, two recent deletion mapping studies of 11q13 on 59 sporadic neuroendocrine neoplasms of different locations provided evidence that a second tumor suppressor gene in the interval between D11S4907 and D11S987 telomeric of the MEN1 gene locus might also be involved in the tumorigenesis of sporadic neuroendocrine neoplasms.^30,31

Another interesting finding of our study is that the MEN1 gene mutations encountered were not restricted to foregut tumors, as recently reported by Toliat et al¹⁷ and suggested by Debelenko et al.¹⁶ Indeed, the frequencies of mutations in foregut and mid/hindgut tumors were very similar (15.2% versus 16.6%), despite the fact that the number of investigated mid/hindgut tumors was much smaller than that of the foregut tumors (6 versus 46). It remains to be seen, however, if NET of the hindgut (colon and rectum) also contain somatic MEN1 gene mutations, because we have investigated only one colonic neuroendocrine carcinoid tumor and Toliat et al investigated only four tumors, including one NET of the appendix.

Analysis of the published data and that presented here makes it clear that missense mutations are the most frequently encountered mutation type (14 tumors), followed by deletions (8 tumors), stop codon mutations (6 tumors), and insertions (3 tumors). Furthermore, the majority of alterations are encountered in the 5' part of the coding region of the MEN1 gene. No correlation seems to exist between tumor type and a particular type or location of mutation in the MEN1 gene. Likewise, no association between type or location of the mutation and clinical course could be established.

From all of the evidence discussed above, it appears that the most useful application of MEN1 gene mutation analysis would be to identify MEN1 gene carriers among patients with clinically sporadic EPT or NET. As a case in point, one individual with a NET of the lung in our series turned out to be a MEN1 gene carrier. Based on clinical experience it is estimated that the de novo mutation rate of MEN1 is approximately 10% and that 1.5% of patients suffering from gastrointestinal NET are in fact MEN1 gene carriers.³² Thus, we recommend testing all patients suffering from multiple NET or a combination of NET or EPT and other MEN1-associated lesions of the skin, adipose tissue, or the adrenal cortex for MEN1 gene mutations.

	Acknowledgements

 
We thank S.C. Chandrasekharappa of the National Institutes of Health (Bethesda, MD) for providing the c10B11 cosmid probe and M. Mihatsch, G. Sauter and M. Kasper of the University of Basel and C. Eberle of the University of Zürich for frozen tissue samples. We thank H. Neff and N. Wey for photographic and computer-assisted reproductions.

	Footnotes

 
Address reprint requests to Dr. Paul Komminoth, Division of Cell and Molecular Pathology, Department of Pathology, University of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland. E-mail: paul. komminoth{at}pty.usz.ch

Supported by the Swiss Cancer League (SKL 649-2-1998 to PK and JR) and the Swiss National Science Foundation (31–53625.98 to PK and EJMS).

Accepted for publication November 5, 1998.

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