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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2627-2630
Copyright © 1998 by The Endocrine Society

Original Studies

Alterations of the MEN1 Gene in Sporadic Parathyroid Tumors1

Filip Farnebo, Bin Tean Teh, Soili Kytölä, Ann Svensson, Catherine Phelan, Kerstin Sandelin, Norman W. Thompson, Anders Höög, Günther Weber, Lars-Ove Farnebo and Catharina Larsson

Department of Molecular Medicine, Endocrine Tumor Unit (F.F., B.T.T., A.S., C.P., C.L.), Department of Molecular Medicine, Clinical Genetics Unit (G.W.), Department of Clinical Pathology (A.H.) and Department of Surgery (F.F., A.S., K.S., L.-O.F.), Karolinska Hospital, S-171 76 Stockholm, Sweden; the Department of Clinical Genetics, Oulu University Hospital (S.K.), Kajaanintie 50, 90220 Oulu, Finland; and the Department of Surgery, University of Michigan Hospital (N.T.), TC 2920-D, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Dr. Filip Farnebo, Department of Molecular Medicine, Endocrine Tumor Unit, Karolinska Hospital CMM L8:01, S-171 76 Stockholm, Sweden. E-mail: filip.farnebo{at}cmm.ki.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Primary hyperparathyroidism is a common endocrine disease that also occurs in a number of inherited disorders, including multiple endocrine neoplasia type 1 (MEN1). Loss of heterozygosity (LOH) in the MEN1 region on chromosome 11q13 has been found in 30% of sporadic parathyroid tumors, making the recently cloned MEN1 gene a prime candidate for involvement in parathyroid tumorigenesis. Using LOH and single strand conformation analysis, we screened 45 sporadic tumors from 40 patients for alterations involving the MEN1 gene. Thirteen tumors showed LOH at 11q13, and in 6 of these cases, somatic mutation of the MEN1 gene was detected. In tumors without LOH, no mutations were detected. The mutations consisted of 3 small deletions, 1 insertion, and 2 missense mutations that had not been reported in MEN1 patients or parathyroid tumors previously. Using messenger ribonucleic acid in situ hybridization, the expression of the MEN1 gene was studied. There was no difference in expression between normal and tumor tissue. In conclusion, the findings of inactivating mutation in tumors with LOH at 11q13 confirm the role of the MEN1 tumor suppressor gene in a subset of sporadic parathyroid tumors.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
INACTIVATION of tumor suppressor genes by germline and somatic mutations has been found in a wide variety of tumors associated with familial cancer syndromes, such as retinoblastoma (1) and von Hippel-Lindau syndrome (2). Frequently, these mutations are also found in the sporadic counterparts of these tumors. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder characterized by the development of tumors in the parathyroid glands, pancreatic islet cells, anterior pituitary gland, and other tissues. The MEN1 gene, which was mapped to chromosomal region 11q13 (3), was recently identified by positional cloning (4). It contains 1 untranslated exon and 9 translated exons encoding a 610-amino acid protein. It has no homology to previously known proteins, and its function remains unknown. Mutation analysis in MEN1 patients identified mutations in all of the 9 coding exons (4, 5, 6), but no genotype-phenotype correlation has been established (6, 7). The most prominent feature of MEN1 is multiglandular parathyroid disease (90–97% of affected patients) causing hyperparathyroidism (HPT), a common but usually sporadic disorder. Loss of heterozygosity (LOH) for markers in the MEN1 region has been demonstrated not only in MEN1-related parathyroid tumors, but also in up to 30% of sporadic parathyroid tumors (8, 9, 10). Recently, Heppner et al. identified somatic mutations in the MEN1 gene in 7 of 33 analyzed sporadic parathyroid tumors (11).

Using LOH analysis, single strand conformation analysis (SSCA), direct sequencing, and messenger ribonucleic acid (mRNA) in situ hybridization, we have analyzed a panel of tumors to evaluate the role of the MEN1 gene in sporadic primary HPT.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient material

Parathyroid tissue from 31 patients with uniglandular disease, operated on for sporadic primary HPT at the Karolinska Hospital in 1996, and tissue from 9 patients (14 glands) with multiglandular disease, operated on between 1993 and 1996, were snap-frozen in liquid nitrogen after removal and stored at -70 C until analysis. The clinical data for these tumors are summarized in Table 1Go. The patients (32 women and 8 men) had a median age of 64.5 yr at operation (range, 29–83 yr). The preoperative median concentration of serum calcium was 2.85 mmol/L (11.4 mg/dL; reference range, 2.20–2.60 mmol/L), and that of intact PTH was 88 ng/L (reference range, 12–55 ng/L). None of the patients in the multiglandular disease group had a positive family history for any other endocrine disease, nor did they show any clinical sign of other endocrine disorder. The surgical approach was to identify all 4 glands in each patient. The median tumor weight in the uniglandular group was 618 mg (range, 152–2900), and the median weight of the largest gland in patients with multiglandular disease was 1030 mg (range, 250–2710). All patients were normocalcemic postoperatively. High mol wt DNA was prepared from fresh-frozen tumor tissue and peripheral blood leukocytes using standard methods. To prove the representativity of the tumor material, pieces were cut from all specimens for histopathological examination. By semiquantitative evaluation all tumor samples included in the study were shown to contain more than 70% tumor cells.


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  		Table 1. Clinical data for the 45 sporadic parathyroid tumors

 
Thirty-seven of the tumors were also used for expression studies, using mRNA in situ hybridization, together with sections of parathyroid biopsies (<10 mg) from four normocalcemic patients (all women; median age, 52 yr) operated on for thyroid disorders (benign goiter, n = 2; toxic goiter, n = 2). The biopsies had been taken for frozen section verification of parathyroid glands, which had to be removed and implanted in the sternocleidomastoid muscle during thyroidectomy to secure vascularization and function (12). To further expand the in situ study, an additional set of 17 tumors with matching normal biopsies from the same patient were included [used in a previous study (13)]. Informed consent was obtained from all patients, and the study was approved by the ethical committee of the Karolinska Hospital.

SSCA

The 9 coding exons of the gene were amplified using 15 different fragments of 200–300 bp each, as previously described (5). Genomic DNA (50 ng) was amplified using the standard PCR conditions in 50 mmol/L KCl; 10 mmol/L Tris-HCl (pH 9.0); 1.5 mmol/L MgCl2 (Promega, Madison, WI); 0.2 mmol/L deoxy (d)-TTP, dCTP, and dGTP; 0.05 mmol/L dATP; and [{alpha}-32P]dATP (Amersham) at 1 µCi/reaction and 2 U Taq DNA polymerase (Promega) in a final volume of 15 µL. Thermocycling conditions consisted of 30 cycles of 1 min at 94 C, 1 min at 62 C, and 1 min at 72 C, followed by 1 cycle of 5-min extension at 72 C. The PCR products were then electrophoresed in 25% MDE (FMC, Rockland, ME) gels at room temperature for 12 h at 6–8 watts. Gels were dried before autoradiography was carried out. Positive controls were available for all exons except 2 (exons 6 and 8).

Direct DNA sequencing

All SSCA-shifted bands were excised from the MDE gel and placed in 50 µL ddH2O at 37 C for 1 h. A 5-µL aliquot of this solution was then amplified in a 50-µL reaction with the following components: 50 mmol/L KCl; 10 mmol/L Tris-HCl (pH 9.0); 1.5 mmol/L MgCl2 (Promega); 0.2 mmol/L dTTP, dCTP, dGTP, and dATP; and 15 U Taq DNA polymerase (Promega). The purified PCR products were sequenced from both strands. For sequence reactions, one of the PCR primers was biotinylated at the 5'-end. Solid phase sequence reactions with 35S-labeled dATP were performed using Dynabeads (Dynal, Chantilly, VA) and Sequenase (U.S. Biochemical Corp., Cleveland, OH) according to the manufacturers’ manuals, followed by terminal deoxynucleotidyl transferase (Boehringer Mannheim, Indianapolis, IN) treatment for 15 min with the addition of 0.2 mmol/L dNTPs. Sequence reactions were then run on 6% denaturing polyacrylamide gels and autoradiographed overnight. Mutations were confirmed to be somatic using direct sequencing of the constitutional DNA.

LOH analysis

Two microsatellite markers located close to and flanking the MEN1 gene on chromosome 11q13 were selected: D11S449 and PYGM (14). PCR were performed according to standard procedures, and the PCR products were electrophoresed on polyacrylamide gel followed by autoradiography. LOH was defined as a complete absence or reduced signal intensity for one of the constitutional alleles in the tumor tissue that could be detected visually.

mRNA in situ hybridization

Preparation of probes. Two oligonucleotide probes with sequences complementary to mRNAs encoding for menin (nucleotides 2324–2364 and 7686–7726; GenBank/EMBL Data Bank accession no. U93237) (4) and one for glycerol aldehyde phosphate dehydrogenase (GAPDH; nucleotides 1149–1193; GenBank/EMBL Data Bank accession no. M33197) (15) were synthesized (Geneset, Paris, France). The oligonucleotides were labeled at the 3'-end with [{alpha}-35S]dATP (New England Nuclear, Boston, MA) using terminal deoxynucleotidyl transferase (Amersham Life Science, Cleveland, OH). The labeled probes were purified using the QIAquick nucleotide removal kit (Qiagen, Germany).

In situ hybridization. Cryostat sections, 14 µm thick, were cut at -20 C and thaw-mounted onto SuperFrost Plus slides (Menzel-Gläser). Hybridization was essentially performed as previously described (13). Negative control experiments using a sense probe were performed.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Forty-five matched blood-tumor pairs from 40 patients with sporadic primary HPT were screened for mutations and LOH of the MEN1 gene (Fig. 1Go). The clinical information regarding the tumors is summarized in Table 1Go, and the results for the 13 cases in which alterations were detected are detailed in Table 2Go. LOH analysis was performed using markers located within a 600-kb region and flanking the MEN1 gene (cen-[PYGM-MEN1-D11S449]-tel). All cases were informative for at least 1 marker, and in 13 of the 45 tumors (29%), LOH was detected. SSCA screening detected variants in 8 of the 45 tumors analyzed. Two of these were due to a polymorphism in exon 3, codon 171 (4), and were also present in the corresponding constitutional DNA. In the remaining 6 cases, the normal nucleotide sequence was found in the constitutional DNA, thus confirming the mutation as somatic. The types of mutation detected included small deletions (n = 3) and insertions (n = 1), resulting in frame shifts or deletion of one amino acid, and missense mutations (n = 2) causing incorporation of a different amino acid.



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  		Figure 1. a, Direct sequencing of the tumor and the constitutional DNA from patient 155 revealed a nucleotide shift in the tumor, G{Rightarrow}T, giving rise to a missense mutation. b, LOH analysis of the same tumor with marker D11S449, showing LOH.

 

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  		Table 2. Sporadic parathyroid tumors with somatic mutation and/or LOH

 
The six cases with somatic mutation all showed LOH in the MEN1 region, in agreement with the two-hit model for inactivation of the MEN1 gene. In addition, no difference was seen between cases with and without MEN1 mutations and 11q13 LOH with regard to tumor weight, serum calcium, PTH, age at operation, or number of affected glands (Table 1Go). In four of the nine cases with multiglandular disease, more than one pathological gland was analyzed. One of the tumors from patient 61 showed both LOH and a missense mutation, whereas in the other tumor from the same patient, no alterations were detected (Table 2Go).

Using mRNA in situ hybridization, the expression of the MEN1 gene was determined in normal and tumor tissue. A total of 54 tumors and 4 normal parathyroid glands were analyzed, including 37 of the tumors from the mutation analysis and an additional set of 17 tumors with matched normal biopsies. The expression of GAPDH was analyzed to exclude significant reduction of mRNA due to ribonuclease activity in the tumors, and in addition, human testis was included as a positive control in the experiments. The level of expression was generally low in the parathyroid samples, and equal results were obtained with the 2 oligonucleotide probes, located in different parts of the gene. Furthermore, the expression was similar in normal and tumor tissue and in tumors with and without alteration of the MEN1 gene (Fig. 2Go).



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  		Figure 2. Autoradiography films from the mRNA in situ study. Examples of MEN1 gene expression in sporadic parathyroid tumors with no alteration of the MEN1 gene (a), LOH in the MEN1 region (b), and LOH and somatic mutation in the MEN1 gene (c) are shown. Control experiments: GAPDH in a parathyroid tumor (d), MEN1 expression in human testis (e), and a parathyroid tumor hybridized with a sense probe (f).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study demonstrates the involvement of the MEN1 gene in a subset of parathyroid tumors. Thirteen of the 45 tumors (29%) showed LOH, of which 6 (46%) were found to have MEN1 gene mutations. A similar relationship between the frequency of allelic loss and mutations has recently been published by Heppner et al. (11). None of the mutations we found has previously been reported in either MEN1 patients or sporadic parathyroid tumors. The mutations include 3 deletions and 1 insertion, which most likely give rise to truncated proteins resulting in loss of function of the gene. Taken together, these results are compatible with Knudson’s 2-hit mutation theory. In 7 of the tumors with LOH, no MEN1 mutation was detected. However, mutations that were beyond our detection might still exist in these tumors. The SSCA method employed in the mutation screening has an expected detection rate of 60–70%. It is also possible that some mutations lie in the regulatory or untranscribed regions of the gene. For comparison, using the SSCA method, we detected a constitutional MEN1 mutation in 50–60% of familial cases (Teh, B. T., F. Farnebo, C. Phelan, J. Cardinal, D. Cameron, M. Edwards, M. Epsein, D. Hurley, F. Alford, J. J. Shepherd, C. Larsson, S. Kytölä, L. Tranebjaerg, R. Jorde, J. Leistl, P. Salmela, S. Khodaei, F. Parente, M. Nordenskjöld, G. Weber, L. Bergman, N. Hayward, S. Grimmond, G. Silins, M. Walters, C. Stewart, B. Skogseid, K. Öberg, J. Menon, A. Khir, T. T. Tan, S. P. Chan, A. Zaini, B. A. K. Khalid, K. Sandelin, N. Thompson, M.-L. Brandi, M. Waugh, J. Stock, A. Beckers; submitted).

The frequency of mutations and LOH was equal in tumors from patients with uniglandular and multiglandular diseases. In the multiglandular group, no constitutional MEN1 mutations were identified, and one patient was shown to have a somatic MEN1 gene mutation in only one of two pathological glands. In the other gland, other genetic alterations might be responsible. No histopathological difference was noted between these two tumors, except that the tumor showing LOH and mutation was significantly larger (618 vs. 175 mg). The clinical course of this patient has been uneventful. This finding further strengthens the view that multiglandular parathyroid disease is not always MEN1, but may involve other genetic pathways, where the MEN1 gene may or may not participate. Alternatively, tumorigenesis in multiglandular disease may be caused by independent genetic events.

Normally, the expression pattern for a mutated tumor suppressor gene would be decreased in tumors that lacked one or two alleles due to mutation or LOH (1). In both situations, the difference in expression is visible between matching normal and tumor tissues. In the present study, however, there was no difference in expression between normal and tumor tissues, including tumors with and without LOH, and those with both LOH and mutation. Therefore, we expanded the study to include an additional set of sporadic primary parathyroid tumors with matching normal biopsies from the same patient (13). The level of expression remained uniform, and no difference between the tumors and the biopsies could be shown. In cases with LOH, one might speculate that the loss of one allele causes up-regulation of the other. For example, in basal cell carcinoma, inactivating mutations are associated with overexpression of the involved tumor suppressor gene PTCH (16). Alternatively, it might suggest the existence of an alternately spliced form that plays a more important role in the tumorigenesis of the parathyroid but was not detected by the two probes we used. For example, an alternatively spliced form of the FHIT gene, recently cloned from the t(3;8) breakpoint of a familial renal cell carcinoma family, was found to be expressed in normal kidney tissues and cell lines, but have loss of expression in familial and metastatic renal cell carcinoma (17). A better interpretation and correlation of our results might be possible when the function(s) of the MEN1 gene in normal and tumor tissues is known.

In summary, we have characterized 6 mutations in 45 investigated tumors, all of which were confined to tumors that had lost the other chromosome 11q13 allele. These data confirm the role of the MEN1 gene in a subgroup of sporadic parathyroid tumors. As most sporadic parathyroid tumors do not show LOH at 11q13, mutations in genes other than MEN1 have to be sought to explain the development of the majority of parathyroid tumors.


   Footnotes
 
1 This work was supported by the Hagberg Foundation, the Swedish Medical Research Council, the Swedish Cancer Society, the Cancer Society of Stockholm, the Gustav V Jubilee Fund, the Martin Rind Foundation, the Sigurd and Elsa Goljes Foundation, the Fredrik and Ingrid Thuring Foundation, and the Torsten and Ragnar Söderberg Foundations. Back

Received December 19, 1997.

Revised February 12, 1998.

Accepted February 26, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Horowitz JM, Yandell DW, Park SH, et al. 1989 Point mutational inactivation of the retinoblastoma antioncogene. Science. 243:937–940.[Abstract/Free Full Text]
  2. Latif F, Tory K, Gnarra J, et al. 1993 Identification of the von Hippel-Lindau disease tumor supressor gene. Science. 260:1317–1320.[Abstract/Free Full Text]
  3. Larsson C, Skogseid B, Öberg K, Nakamura Y, Nordenskjöld M. 1988 Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature. 332:85–87.[CrossRef][Medline]
  4. Chandrasekharappa SC, Guru SC, Manickam P, et al. 1997 Positional cloning of the gene for multiple endocrine neoplasia-type I. Science. 276:404–407.[Abstract/Free Full Text]
  5. The European Consortium on MEN1. 1997 Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. Hum Mol Genet. 6:1177–1183.[Abstract/Free Full Text]
  6. Agarwal SK, Kester MB, Debelenko LV, et al. 1997 Germline mutations of the MEN1 gene in familial endocrine neoplasia type 1 and related states. Hum Mol Genet. 6:1169–1175.[Abstract/Free Full Text]
  7. Teh BT, Zedenius J, Kytölä S, et al. Thymic carcinoids in multiple endocrine neoplasia type 1. Ann Surg. In press.
  8. Thakker RV, Bouloux P, Wooding C, et al. 1989 Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. N Engl J Med. 318:658–662.[Abstract]
  9. Byström C, Larsson C, Blomberg C, et al. 1990 Localization of the MEN1 gene within a small region of 11q13 by deletion mapping in tumors. Proc Natl Acad Sci USA. 87:1968–1972.[Abstract/Free Full Text]
  10. Friedman E, De Marco L, Gejman P, et al. 1992 Allelic loss from chromosome 11 in parathyroid tumors. Cancer Res. 52:6804–6809.[Abstract/Free Full Text]
  11. Heppner C, Kester MB, Agarwal SK, et al. 1997 Somatic mutations of the MEN1 gene in parathyroid tumors. Nat Genet. 16:375–378.[CrossRef][Medline]
  12. Olson Jr JA, DeBenedetti MK, Baumann DS, Wells Jr SA. 1996 Parathyroid autotransplantation during thyroidectomy. Results of long-term follow-up. Ann Surg. 223:472–478.[CrossRef][Medline]
  13. Farnebo F, Enberg U, Grimelius L, et al. 1997 Tumor specific decreased expression of the calcium sensing receptor (CaR) mRNA in sporadic primary hyperparathyroidism. J Clin Endocrinol Metab. 82:3481–3486.[Abstract/Free Full Text]
  14. The European Consortium on MEN. 1 1997 Construction of a 1.2 Mb sequence-ready contig of chromosome 11q13 encompassing the multiple endocrine neoplasia type 1 (MEN1) gene. Genomics. 44:94–100.[CrossRef][Medline]
  15. Tokunaga K, Nakamura Y, Sakata K, et al. 1987 Enhanced expression of a glyceraldehyde-3-phosphate dehydrogenase gene in human lung cancers. Cancer Res. 47:5616–5619.[Abstract/Free Full Text]
  16. Gailani MR, Ståhle-Bäckdahl M, Leffell DJ, et al. 1997 The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 14:78–81.
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