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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2631-2634
Copyright © 1998 by The Endocrine Society

Original Studies

Analysis of Loss of Heterozygosity on Chromosome 11 and Infrequent Inactivation of the MEN1 Gene in Sporadic Pituitary Adenomas1

Chisato Tanaka, Takehiko Kimura, Peng Yang, Maki Moritani, Takashi Yamaoka, Shozo Yamada, Toshiaki Sano, Katsuhiko Yoshimoto and Mitsuo Itakura

Otsuka Department of Clinical and Molecular Nutrition (C.T., M.M., T.Y., K.Y., M.I.), First Department of Internal Medicine (T.K.), and First Department of Pathology (P.Y., T.S.), University of Tokushima School of Medicine, 3–18-15 Kuramoto-cho, Tokushima 770-8503; and the Department of Neurosurgery, Toranomon Hospital (S.Y.), 2–2-2 Toranomon, Minato-ku, Tokyo 105-0001, Japan

Address all correspondence and requests for reprints to: Katsuhiko Yoshimoto, M.D., Ph.D., Otsuka Department of Clinical and Molecular Nutrition, University of Tokushima School of Medicine, 3–18-15 Kuramoto-cho, Tokushima 770-8503, Japan.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To investigate the role of tumor suppressor genes in sporadic pituitary adenomas, we first analyzed loss of heterozygosity on 11q13 with microsatellite analysis in 31 tumors. Loss of heterozygosity on 11q13 was detected in 1 mixed GH/PRL adenoma, and the somatic 22-bp deletion of the multiple endocrine neoplasia type 1 (MEN1) gene encoding menin was detected in this tumor. Trisomy 11 suggested by the decreased mean allelic ratios of 66% or 65% for 16 or 13 microsatellite markers, respectively, in 2 of 31 pituitary adenomas was confirmed by interphase fluorescence in situ hybridization. Screening for mutations of the MEN1 gene did not find mutations with PCR-single strand conformation polymorphism analysis in other pituitary adenomas retaining heterozygosity on 11q13.

Based on these, it is concluded that inactivation of the MEN1 gene comprises a rare etiology for tumorigenesis of the pituitary gland, and that trisomy 11 or another gene(s) may contribute to the pathogenesis of sporadic pituitary adenomas.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PITUITARY tumors are usually sporadic, but a significant minority presents as a component of multiple endocrine neoplasia type 1 (MEN-1) and, rarely, as a familial pituitary adenoma. The MEN1 gene on 11q13 was recently identified (1, 2). That the MEN1 gene is a tumor suppressor gene was supported by the demonstration of allelic loss of polymorphic marker DNAs on 11q13 in most of MEN-1-associated tumors of the parathyroid, pancreas, and pituitary (3, 4, 5, 6, 7, 8, 9). In MEN-1, germ-line mutations in the MEN1 gene have been found in most patients with familial and sporadic MEN-1 (1, 2, 10). However, the molecular pathogenesis of the majority of sporadic pituitary tumors is largely unknown (11).

Although a significant incidence of loss of heterozygosity (LOH) on chromosome 11 in 26–38% and 19–44% of sporadic parathyroid tumors (3, 8, 9) and pancreatic endocrine tumors (5, 12), respectively, was reported, the incidence of LOH on chromosome 11 in sporadic pituitary adenomas was reported to be as low as 0 of 3 (4), 0 of 5 (12), 2 of 26 (3), 1 of 7 (13), and 16 of 88 (14). To determine the role of the MEN1 gene in pituitary tumorigenesis, we analyzed LOH on chromosome 11 and screened mutations of the MEN1 gene with PCR-single strand conformation polymorphism (SSCP) analysis and determined DNA sequences of aberrantly shifted bands by PCR-SSCP analysis.


   Materials and Methods
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 Materials and Methods
Results
 Discussion
 References
 
Tissue samples and extraction of DNA from tissues

Tissue samples of pituitary adenomas from 31 patients were obtained at transsphenoidal surgery. Peripheral blood samples were collected from these patients. The clinical features, including clinical diagnosis and Hardy’s classification, of 31 patients with sporadic pituitary adenomas were reported previously (15). These tumors included 10 somatotroph adenomas, 2 mixed GH/PRL adenomas, 6 prolactinomas, 2 thyrotroph adenomas, 1 corticotroph adenoma, and 10 endocrine inactive adenomas. DNA was extracted from frozen tumor sections as follows. In frozen tumor sections, tumor and normal tissues were separated under a microscope by cutting them into small pieces using a razor blade. We microscopically confirmed that tumor tissues were scarcely contaminated with normal tissues. Small pieces were treated with proteinase K in 100 µL digestion buffer [50 mmol/L Tris-HCl (pH 8.0), 0.5 mmol/L ethylenediamine tetraacetate, and 0.5% Tween-20] at 37 C overnight. Genome DNA was obtained after phenol-chloroform extraction and ethanol precipitation.

Detection of LOH by fluorescent microsatellite analysis

LOH in tumors was examined with regard to 10 microsatellite markers located on 11q13: centromere-D11S480,D11S1883, D11S457, PYGM,D11S1783, D11S449, D11S1889, D11S913, D11S534, and D11S527-telomere (16). The MEN1 gene is localized between PYGM and D11S449. The linear ordering of these markers is based on published data (16). With regard to samples showing decreased allelic ratios, 10 additional markers on chromosome 11 were analyzed for better characterization of the pattern and extent of allelic deletion for these chromosomal regions (Table 1Go).


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  		Table 1. Allelic ratios of markers on chromosome 11 in pituitary adenomas

 
Microsatellite markers were PCR amplified from 31 paired normal and tumor DNA samples. PCR amplification, gel electrophoresis, data collection, and analysis were carried out as previously described (17). Each fluorescent peak was assessed by the peak height. The ratio of alleles 1 and 2 was calculated for leukocyte DNA as the representative normal tissue and the tumor DNA. Calculation was made by T1:T2/N1:N2, where T1 and N1 were the peak height values of the smaller allele product peak for the adenoma DNA and the normal leukocyte DNA, respectively, and T2 and N2 were the peak height values of the taller allele product from the adenoma DNA and the normal leukocyte DNA, respectively.

PCR-SSCP and DNA sequencing

The coding sequence, including 9 coding exons and 16 splice junctions, of the MEN1 gene was screened with PCR-SSCP (18). We synthesized 12 sets of PCR primers based on the published MEN1 gene sequence (GenBank accession no. U93236) as previously described (18). Three conditions of 8% polyacrylamide gels containing 0%, 5%, or 10% glycerol were routinely used for PCR-SSCP screening for each PCR product.

Aberrantly shifted bands detected with PCR-SSCP analysis were excised from dried polyacrylamide gels using a razor blade and eluted in distilled water at 55 C for more than 30 min. DNA sequences of at least five cloned PCR products were determined, as previously described (15), in sense and antisense directions by fluorescence-based dideoxy cycle sequencing.

Interphase fluorescence in situ hybridization (FISH) analysis

Interphase FISH was performed as described previously (17). Briefly, tissue sections of 6 µm in thickness from paraffin blocks were deparaffinized. After protein digestion, the biotin-labeled {alpha}-satellite probe for chromosome 11 (D11Z1, Oncor, Gaithersburg, MD) was directly added to the tissue sections, hybridized, and washed. After the in situ hybridization, tissue sections were counterstained with propidium iodide. The number of hybridized probes per nucleus detected with fluorescein-conjugated avidin under confocal fluorescent microscopy was counted in at least 100 nuclei in each sample.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
All patients were informative for 5 or more loci in 10 loci analyzed on 11q13. Of 31 tumors, the decrease in the fluorescent intensity of 1 allele in tumor DNA compared to that in matched patients’ leukocytes was detected in 3 pituitary adenomas (Table 1Go). The reproducibility of the allelic ratios for these samples was confirmed by 2–4 independent PCR amplifications for each sample. Genotyping of additional markers on 11p and 11q showed loss of the almost entire long arm, including 11q13, in sample 12 (mixed GH/PRL adenoma) (Fig. 1CGo and Table 1Go). Allelic ratios of markers on the short arm of chromosome 11 in sample 12 of 84–90% suggested the retained heterozygosity (Table 1Go).



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  		Figure 1. Representative example of decreased allelic ratios at the markers on chromosome 11 in pituitary adenomas. The results for samples 3, 13, and 12 are shown in A, B, and C, respectively. DNAs from leukocytes (WBC) and a pituitary adenoma (tumor) were analyzed for each sample. Arrowheads denote shorter allele product peaks in tumors compared to leukocytes. The corresponding allelic ratio value (percentage) is shown for each set of profiles.

 
Twelve PCR products covering the entire coding region of the MEN1 gene were screened for mutations in the MEN1 gene with PCR-SSCP. One aberrantly shifted band was detected in sample 12 in its remaining allele when exons 5 and 6 of the MEN1 gene were amplified (Fig. 2Go). No aberrantly shifted bands were detected in leukocyte DNA in sample 12. Sequencing of this tumor DNA revealed a 22-bp deletion at nucleotides 5199–5220 including 19 bp in exon 5 and 3 bp in intron 5, resulting in a premature stop codon. No tumor-specific abnormal shifts were observed in 30 other tumors under 3 different SSCP conditions. We detected 2 polymorphisms, which were reported by Chandrasekharappa et al. (1); 1 synonymous polymorphism at codon 418 of GAC or GAT with the former in 50% (31 of 62 alleles) and another polymorphism at codon 541 of GCA or ACA encoding alanine or threonine, respectively, with the former in 26% (16 of 62 alleles) of the Japanese.



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  		Figure 2. PCR-SSCP analysis of the MEN1 gene in pituitary adenomas. Genomic DNAs from pituitary adenomas were amplified by PCR using primers for the MEN1 gene. Results of primer set 6 (18 ) including exons 5 and 6 of the MEN1 gene in seven representative pituitary adenomas are shown. Variant bands were observed in sample 12.

 
The decreased mean allelic ratios of 66% and 65% in samples 3 (somatotroph adenoma) and 13 (prolactinoma; Table 1Go and Fig. 1Go, A and B), respectively, with regard to multiple microsatellite markers on the entire chromosome 11 suggested the possibility of trisomy 11. Trisomy 11 was examined using the interphase FISH method with the {alpha}-satellite probe for chromosome 11. Intact and independent nuclei were examined with confocal fluorescent microscopy, and 3 signals of the centromere of chromosome 11 were detected in 61% and 73% of examined cells in 2 samples (samples 3 and 13) that showed decreased allelic ratios (Table 2Go). On the other hand, we detected 2 signals at the highest frequency in control samples, including sample 25, which retained both alleles with allelic ratios of more than 90% at microsatellite analysis, and sample 12, which showed loss of the almost entire long arm (Table 1Go).


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  		Table 2. Percent distribution of different numbers of positive nuclear signals in pituitary adenomas using an {alpha}-satellite probe specific to chromosome 11

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The incidence of allelic loss of chromosome 11 was 26–38% in a large number of sporadic parathyroid adenomas (3, 8, 9) and 19–44% in sporadic pancreatic endocrine tumors (5, 12). This loss typically involves the region to which the MEN1 gene was mapped. The MEN1 gene could be a target for the somatic inactivation of both alleles that occurs in a clonal precursor cell and thus may contribute to the development of some sporadic parathyroid and pancreatic endocrine tumors. Recently, Heppner et al. (19) reported that somatic MEN1 mutations were found in 7 of 33 parathyroid tumors not associated with MEN-1, and all parathyroid tumors with MEN1 mutations showed LOH on 11q13. The frequency of LOH on 11q13 in sporadic pituitary adenomas, however, was reported to be lower than that in sporadic parathyroid and pancreatic endocrine tumors (3, 5, 12, 13, 14).

We examined LOH on 11q13 in human pituitary adenomas. We detected decreased allelic ratios on chromosome 11 in 3 of 31 pituitary adenomas. We found LOH on 11q13 in 1 sample and trisomy of chromosome 11 in 2 samples. A somatic mutation of the MEN1 gene was found by PCR-SSCP analysis in the DNA sample showing LOH on 11q13. The polymorphic changes in D418D (GAC/GAT) and A541T (GCA/ACA) were frequently detected by PCR-SSCP analysis. We did not, however, find any tumor-specific somatic mutations of the MEN1 gene in the remaining 30 pituitary adenomas. Although the sensitivity of PCR-SSCP analysis is less than 100%, we detected germ-line mutations of the MEN1 gene in patients with familial or sporadic MEN-1 by PCR-SSCP analysis (18). In addition, DNA samples from leukocytes in separate three families with familial pituitary adenoma, in which extensive PCR-SSCP analysis could not find aberrant bands, were sequenced for exons 2–10, but no mutations were found (18). However, we could have missed mutations in the 5'- and 3'-noncoding regions of this gene. Nevertheless, our data suggest that the MEN1 gene plays a minor role in the genesis of sporadic pituitary adenomas.

The incidence of LOH on 11q13 of only 1 in 33 sporadic pituitary adenomas is lower than that in sporadic parathyroid tumors (3, 8, 9) and sporadic pancreatic endocrine tumors (5, 12). The possibility that sporadic pituitary adenomas could arise due to the inactivation of the wild-type allele of the MEN1 gene via point mutations or small deletions rather than via the loss of a large segment of 11q13 was ruled out because pituitary adenomas showing no LOH on 11q13 did not show any mutations of the MEN1 gene by PCR-SSCP analysis.

The unexpected uniform decrease in the allelic ratios of 54–66% with small SD values with regard to all 18 microsatellite markers on the entire chromosome 11 in 2 human pituitary adenomas strongly suggested the presence of trisomy 11, because trisomy should theoretically lead to the decreased allelic ratio of 50%. Trisomy 11 has been reported in many cases, including acute lymphoblastic leukemia and acute myeloid leukemia (20), but only 1 case of GH-producing pituitary adenoma with multiple trisomies 3, 5, 7, 11, 12, 13, 17, and 19 was reported (21). Recently, we detected uniformly decreased allelic ratios of close to 50% on chromosome 12 in 8 of the same 31 pituitary adenomas (17). These numerical aberrations of chromosomes, including relatively frequent trisomy, can be etiological for the tumorigenesis of pituitary tumors through changing the gene doses.

Inactivation of the MEN1 gene was thus shown not to be a common etiology for tumorigenesis of the pituitary gland. Further studies, such as comparative genomic hybridization and/or genome-wide allelotyping, are necessary to find etiological oncogene(s) and/or tumor suppressor gene(s) for pituitary tumorigenesis.


   Acknowledgments
 
We thank Miss Takako Nakamura for technical assistance, Dr. Hiroyuki Iwahana for continuous support, and Dr. Andrew Arnold for helpful discussion.


   Footnotes
 
1 This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan, and a grant from Otsuka Pharmaceutical Factory for Otsuka Department of Clinical and Molecular Nutrition, University of Tokushima School of Medicine. Back

Received October 27, 1997.

Revised March 2, 1998.

Accepted March 9, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Chandrasekharappa SC, Guru SC, Manickam P, et al. 1997 Positional cloning of the gene for multiple endocrine neoplasia type 1. Science. 276:404–407.[Abstract/Free Full Text]
  2. Lemmens I, Van de Ven WJM, Kas K, et al. 1997 Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. Hum Mol Genet. 6:1177–1183.[Abstract/Free Full Text]
  3. Byström C, Larsson C, Blomberg C, et al. 1990 Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. Proc Natl Acad Sci USA. 87:1968–1972.[Abstract/Free Full Text]
  4. Bale AE, Norton JA, Wong EL, et al. 1991 Allelic loss on chromosome 11 in hereditary and sporadic tumors related to familial multiple endocrine neoplasia type 1. Cancer Res. 51:1154–1157.[Abstract/Free Full Text]
  5. Debelenko LV, Zhuang Z, Emmert-Buck MR, et al. 1997 Allelic deletions on chromosome 11q13 in multiple endocrine neoplasia type 1-associated and sporadic gastrinoma and pancreatic endocrine tumors. Cancer Res. 57:2238–2243.[Abstract/Free Full Text]
  6. Dong Q, Debelenko LV, Chandrasekharappa C, et al. 1997 Loss of heterozygosity at 11q13: analysis of pituitary tumors, lung carcinoids, lipomas, and other uncommon tumors in subjects with familial multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 82:1416–1420.[Abstract/Free Full Text]
  7. Thakker RV, Pook MA, Wooding C, Boscaro M, Scanarini M, Clayton RN. 1993 Association of somatotrophinomas with loss of alleles on chromosome 11 and gsp mutations. J Clin Invest. 91:2815–2821.
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  11. Shimon I, Melmed S. 1997 Pituitary tumor pathogenesis. J Clin Endocrinol Metab. 82:1675–1681.[Free Full Text]
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