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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 11 4113-4117
Copyright © 2000 by The Endocrine Society

Original Studies

Rare Somatic Inactivation of the Multiple Endocrine Neoplasia Type 1 Gene in Secondary Hyperparathyroidism of Uremia1

Hideki Tahara, Yasuo Imanishi, Tomomi Yamada, Yoshihiro Tsujimoto, Tsutomu Tabata, Takashi Inoue, Masaaki Inaba, Hirotoshi Morii and Yoshiki Nishizawa

Division of Metabolism, Endocrinology, and Molecular Medicine, Department of Internal Medicine, Osaka City University Graduate School of Medicine (H.T., Y.I., T.Y., M.I., H.M., Y.N.), Osaka 545-8585, Japan; and Inoue Hospital (Y.T., T.T., T.I.), Suita 564-0053, Japan

Address all correspondence and requests for reprints to: Dr. Hideki Tahara, M.D., Ph.D., Department of Internal Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan. E-mail: hideki-t{at}ka2.so-net.ne.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The molecular pathway of autonomous growth of the parathyroid glands in uremic patients is poorly understood. Loss of heterozygosity at the recently identified multiple endocrine neoplasia type 1 (MEN1) gene locus on chromosome 11q13 has been found in a subset of parathyroid glands from patients with refractory hyperparathyroidism. To clarify the role of the MEN1 gene in parathyroid tumorigenesis, we analyzed 81 parathyroid glands from 22 Japanese uremic patients for allelic loss on chromosomal arm 11q13 DNA using 3 flanking markers (PYGM, D11S4946, and D11S449) and for mutations of the MEN1-coding exons by PCR-based single strand conformation polymorphism analysis and sequencing. Allelic loss on 11q13 was observed in 6 glands (7%), and 1 of 6 demonstrated a previously unrecognized somatic frameshift deletion (331delG) of the MEN1 gene. This mutation would probably result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and pathological characteristics of hyperparathyroidism were unrelated to the presence or absence of loss of heterozygosity on 11q13 and MEN1 gene mutations. These observations indicate that somatic inactivation of the MEN1 gene contributes to the pathogenesis of uremia-associated parathyroid tumors, but its role in this disease appears to be very limited.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
SECONDARY HYPERPARATHYROIDISM is usually the result of chronic renal insufficiency, and a state of compensatory hypersecretion of PTH may occur in any condition in which there is a tendency toward hypocalcemia. With the progression of renal disease, the total weight of the parathyroid glands may be considerably increased, and the degree of this enlargement correlates to the duration and severity of the renal functional impairment. Histopathological investigations have suggested that parathyroid cells initially increase diffusely with a normal lobular structure (diffuse hyperplasia), and the parathyroid glands then become hyperplastic with some nodules (nodular hyperplasia). The term tertiary hyperparathyroidism is commonly reserved for patients developing spontaneous hypercalcemia due to hyperfunctioning parathyroid tissue that no longer responds to physiological influences and any medical therapy.

Recent evidence based on more detailed studies of parathyroid glands surgically removed from dialysis patients who had severe hyperparathyroidism refractory to medical treatment indicated that abnormal, monoclonal growth does indeed occur in more than 50% of such patients, based on X-chromosome inactivation analysis with the M27ß (DXS255) DNA polymorphism (1). Monoclonality implies that somatic mutation of certain genes controlling cell growth occurred in a single parathyroid cell. Although candidate genes involved in the pathogenesis of these tumors are unknown, a few studies have investigated the chromosomal regions that harbor the putative parathyroid tumor suppressor genes with the loss of heterozygosity (LOH) analysis. Some groups as well as ours reported that LOH on chromosomal arm 11q13 DNA, including the recently isolated multiple endocrine neoplasia type 1 (MEN1) gene (2), was detected in a small group of this disease (3, 4, 5, 6). To determine the role of the MEN1 gene in secondary hyperparathyroidism of uremia, we analyzed LOH on chromosomal arm 11q13 DNA, screened mutations of the MEN1 gene with PCR-single strand conformation polymorphism (SSCP) analysis, and determined the DNA sequence of aberrantly shifted bands by PCR-SSCP analysis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients and tissue samples

We studied 81 glands from 9 male and 13 female Japanese uremic patients with refractory secondary hyperparathyroidism. All patients were treated and operated on at Inoue Hospital (Osaka, Japan). All patients were receiving intermittent hemodialysis treatment for chronic renal failure. Parathyroidectomy was indicated because of severe secondary hyperparathyroidism associated with pruritus, osteitis fibrosa, soft tissue calcifications, hypercalcemia, hypophosphatemia, and/or other symptoms and signs that were resistant to medical treatment (7). The clinical and pathological data are summarized in Table 2Go. The level of serum intact PTH was measured with an Allegro kit (normal range, <60 pg/mL). None of the patients included in this study had a history of neck irradiation or a clinical or family history suggestive of multiple endocrine neoplasia. In all patients, multiple hypercellular parathyroid glands were identified and resected. Gland sizes ranged from 40–7280 mg. These glands were categorized as either nodular hyperplasia or generalized hyperplasia by gross and histopathological criteria (8, 9), as shown in Table 2Go. One parathyroid gland was available for study from 1 patient, 3 glands each were available for study from 4 patients, and 4 glands each were available for study from 17 patients. Peripheral blood leukocytes were available from all patients.


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  		Table 2. Clinical characteristics and LOH on 11q13 of the patients

 
After surgical removal, parathyroid glands were carefully dissected, frozen in liquid nitrogen, and stored at -70 C until extraction of DNA. High molecular weight genomic DNA was extracted from blood and parathyroid tissue by standard methods. Informed consent was obtained from all patients, and the study was approved by the ethical committee of the Osaka City University Hospital.

Allelic loss analyses on chromosome 11q13

Each patient’s matched pair of control leukocyte and tumor DNA was PCR amplified using primers specific for microsatellite markers, PYGM, D11S4946, and D11S449 (Research Genetics, Inc., Huntsville, AL), all of which are on chromosome 11q13 and closely linked to the MEN1 gene (2, 10). Typically, one of each pair of primers was end labeled with [{gamma}-32P]ATP using T4 polynucleotide kinase (New England Biolabs, Inc., Beverly, MA). One hundred nanograms of genomic DNA were then amplified in a 20-µL volume using a reaction mixture containing 1.5 mmol/L MgCl2, 50 mmol/L KCl, 20 mmol/L Tris-HCl (pH 8.4), 200 µmol/L of each deoxynucleotide triphosphate, 0.01 mg/mL BSA, 1.25 pmol 32P end-labeled sense primer, 5 pmol unlabeled antisense primer, and 0.6 U AmpliTaq Gold DNA polymerase (Perkin-Elmer Corp., Norwalk, CT). PCR was carried out for 30–35 cycles in a GeneAmp PCR System 9600 (Perkin-Elmer Corp.). Each cycle consisted of denaturation at 94 C for 60 s, annealing at 63–65 C for 60 s, and extension at 72 C for 2 min for each polymorphism. PCR products were then mixed with formamide gel loading solution, heat denatured at 94 C, separated on a denaturing 6–8% polyacrylamide-32% formamide gel (11), and visualized by autoradiography for 0.5–48 h. Allelic loss was scored as previously described (12).

SSCP analysis. The coding region and splice sites of the MEN1 gene were amplified by PCR using template genomic DNA from parathyroid glands. The DNA sequences of the primers used for amplification, the sizes of the amplified PCR products, and the restriction enzymes to increase the sensitivity of the SSCP analysis are summarized in Table 1Go. Typically, 100 ng DNA were amplified in a 25-µL reaction mixture containing 1.5 mmol/L MgCl2; 50 mmol/L KCl; 20 mmol/L Tris-HCl (pH 8.4); 5% dimethylsulfoxide; 0.01 µg/mL BSA; 200 µmol/L deoxy (d)-TTP, dCTP, and dGTP; 20 µmol/L dATP; 0.1 µL [{alpha}-32P]dATP (3000 Ci/mmol); 20 pmol of each primer; and 1 U AmpliTaq Gold DNA polymerase. PCR was carried out for 35 cycles in a GeneAmp PCR System 9600 (Perkin-Elmer Corp.). Each cycle consisted of denaturation at 94 C for 30 s, annealing at 60–65 C for 30 s, and extension at 72 C for 45 s; for each primer set, the PCR reaction was optimized by adjusting the annealing temperature. PCR products were then digested with the restriction enzymes listed in Table 1Go, thereby increasing the sensitivity of the SSCP analysis. Digested PCR products were heat-denatured, separated on a nondenaturing 6–8% polyacrylamide gel containing 10% glycerol at 6–8 watts overnight at room temperature, and visualized by autoradiography.


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  		Table 1. PCR primer pairs, annealing temperature, restriction enzymes, and the sizes of digested products for MEN1 PCR-SSCP analysis

 
Mutational analysis. Exons 2–10 of the MEN1 gene were sequenced in all parathyroid glands. All exons were amplified and sequenced with the same primers for PCR-SSCP. Briefly, PCR was performed using 100 ng genomic DNA and 20 pmol of each primer, and PCR products were then purified using a QIAquick PCR purification kit (QIAGEN, Chatsworth, CA) following the manufacturer’s protocol. Approximately, 50 ng of the PCR product underwent sequencing using dye-nucleotide unicycle sequencing (Amersham Pharmacia Biotech, Arlington Heights, IL) according to the manufacturer’s instructions. When an abnormal sequence was detected, the corresponding leukocyte DNA was sequenced, and the parathyroid gland DNA was resequenced.

Statistical analysis

All data were expressed as the mean ± SEM. LOH on 11q13 was compared with preoperative serum calcium level, intact PTH level, phosphate level, duration of hemodialysis, and total weight of parathyroid glands using the Mann-Whitney U test. Histological parameters were compared by a standard {chi}2 test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The involvement of tumor suppressor genes is frequently indicated by evidence of allelic loss (LOH) of DNA markers in the target chromosome region. Thus, we first analyzed 81 parathyroid glands for tumor-specific allelic loss of 3 DNA polymorphic loci, all of which are on chromosome 11q13 and closely linked to the MEN1 gene. Among control leukocyte DNA from all 22 patients, 19 cases (86%) were informative (heterozygous) at the PYGM locus, 17 cases (77%) at D11S4946, and 17 cases (77%) at D11S449, respectively. Overall, 6 of the 81 glands (7%) exhibited allelic loss at 1 or 2 of the tested loci. Representative allelic loss data are shown in Fig. 1AGo. Figure 1BGo shows a map of the specific patterns of allelic loss on 11q13 for these 6 parathyroid hyperplasias. All 6 of these glands showed allelic loss at PYGM locus, whereas 1 of 6 glands showed allelic loss at the D11S449 locus, indicating that 1 copy of the MEN1 gene was completely deleted in at least 1 gland (no. 56-T2). It is interesting to note that in 3 patients with 11q13 loss (no. 50, 54, and 56) all 4 glands from each patient did not show allelic losses. This finding emphasizes the independent clonal origins of discrete tumors within the same patient.



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  		Figure 1. Allelic loss of chromosome 11 loci in uremic parathyroid tumors. A, Representative data from patients with uremic hyperparathyroidism showing tumor-specific loss of one allele (indicated by an arrow and an asterisk) at polymorphic loci on chromosome 11. Genomic DNA from each patient’s control leukocytes (N) and parathyroid gland (T) was amplified with oligonucleotide primers flanking simple sequence repeats. Polymorphisms were detected as described in Materials and Methods. Patient numbers are shown at the top. B, Deletion map of chromosomal arm 11q13. Six glands demonstrating chromosomal arm 11q13 loss are illustrated. Top, Case numbers. At a given locus: {square}, tumor-specific allelic loss; {blacksquare}, retention of both alleles; thick bar, constitutional homozygosity.

 
The Mann-Whitney U test and {chi}2 test showed no statistically significant difference (P > 0.05) in duration of hemodialysis, weight of parathyroid glands, clinical parameters, or histopathological categories of generalized vs. nodular hyperplasia between LOH-positive and LOH-negative groups. A summary of the laboratory data and statistical analysis for the two groups is shown in Table 2Go.

Ten PCR products covering the entire coding region of the MEN1 gene were screened for mutations in all of the MEN1 gene-coding exons with PCR-SSCP in every gland. One aberrantly shifted band was detected in 1 gland (T2) from patient 56 (Fig. 2AGo). This gland showed allelic losses at both PYGM and D11S449 loci (Fig. 1BGo), indicating the loss of 1 allele of the MEN1 gene. Sequencing of this parathyroid tissue DNA revealed a 1-bp deletion at nucleotide 331 in exon 2, and its frameshift mutation caused amino acid changes and the premature stop codon formation. This mutation proved to be of somatic origin when the wild-type sequence was identified in control leukocyte DNA of the affected patient (Fig. 2BGo). Because SSCP analysis can miss some mutations, especially in GC-rich genes, we fully sequenced the MEN1 gene coding exons in all 81 glands, and no other mutations were present. The overall frequency of identified the MEN1 gene mutations in the 81 analyzed parathyroid glands of our study was therefore 1.2% (1 of 81).



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  		Figure 2. PCR-SSCP analysis and sequence analysis of the MEN1 gene in uremic parathyroid tumors. A, The PCR-SSCP of exon 2 shows a tumor-specific mobility shift (indicated by an arrow) in the parathyroid tissue DNA from patient 56. B, Identification of a single nucleotide deletion by sequencing of a cloned exon 2 PCR product from the patient whose SSCP pattern is shown in A compared with the wild-type sequence of a corresponding leukocyte DNA. The mutation is 331delG.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Monoclonality is so defined that somatic mutation of certain genes occurring in a single parathyroid cell leads to a selective growth advantage for them and their progeny. Some previous studies revealed the allelic loss of chromosome arm 11q (3, 4, 5, 6), suggesting that this region might include the candidate tumor suppressor gene(s) involved in the tumorigenesis of secondary uremic parathyroid hyperplasia. 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 secondary parathyroid hyperplasias. Recent study reported that somatic mutations of the MEN1 gene were found in 7 of 33 (21%) parathyroid tumors not associated with MEN1, and all parathyroid tumors with MEN1 gene mutations showed LOH on 11q13 (13). In addition, Carling et al. showed that clinical and biochemical characteristics of nonfamilial primary hyperparathyroidism were apparently unrelated to the presence or absence of LOH and the MEN1 gene mutations (14).

We detected LOH on 11q13 in 6 of 81 (7%) parathyroid glands from Japanese uremic patients, and the occurrence of allelic loss is consistent with our previous findings using glands from nonoverlapping and non-Japanese patients (6). Although we detected the MEN1 gene mutation in 1 gland (1 of 81, 1.2%), no mutations were found in the rest of the glands with 11q13 loss. In other recent findings, mutations of the MEN1 gene were found in 2 of 48 glands (4.2%) (15), consistent with the low prevalence of MEN1 inactivation in our study. There are at least 3 possible reasons why MEN1 gene mutations were not seen in lesions with loss of 1 copy of the MEN1 gene. First, mutation outside of the open reading frame may contribute to gene inactivation by interfering with splicing, translation, or decreasing the transcript half-life. Second, there may be MEN1 gene transcription inactivation by promoter mutation or alteration in methylation. There is precedent for this in other tumor suppressor genes, such as VHL, RB, p53, cadherin, and p16, where 1 tumor allele can be inactivated by promoter alterations (16, 17, 18, 19, 20, 21). Third, it is possible that the MEN1 gene is not inactivated in these glands, and the LOH is unmasking a second neighboring tumor suppressor gene locus.

We were unable to find a statistical difference in preoperative serum calcium level, phosphate level, intact PTH level, gland weight, or histopathological criteria between LOH-positive and LOH-negative groups. Our data indicate that loss of 11q13 DNA is not solely a feature of advanced, nodule-type, parathyroid hyperplasias, but is also found in smaller, diffuse hyperplasias.

Considering that most uremic parathyroid tumors do not exhibit LOH on 11q13, mutation of genes other than the MEN1 gene is likely to contribute to tumorigenesis of many parathyroid tumors. The cloned genes to date implicated in parathyroid neoplasia include two oncogenes, PRAD1/cyclin D1 (22, 23) and Ret (24), and two tumor suppressor genes, Rb (25) and p53 (26). Although a previous report showed that PRAD1/cyclin D1 overexpression was found in 18% of parathyroid adenomas by immunostaining (23), Tominaga et al. failed to detect a remarkable overexpression of PRAD1/cyclin D1 in secondary parathyroid hyperplasia, such as that seen in parathyroid adenoma (27). The MEN2A and MEN2B syndromes and familial medullary thyroid carcinoma, which are dominantly inherited cancer syndromes, are all associated with germline mutations of the RET protooncogene. However, a recent study showed no evidence for rearrangement or allelic loss for the RET oncogene in uremic patients with secondary hyperparathyroidism (28). Cryns et al. demonstrated that frequent loss (88%) of chromosomal arm 13q14 and consequent functional inactivation of the RB gene are found in parathyroid carcinomas (25), and that the p53 gene may play a role in a smaller subset (17%) of these parathyroid tumors (26). Recently, Palanisamy et al. performed both comparative genomic hybridization and genome-wide molecular allelotyping on a large group of uremia-associated parathyroid hyperplasias from nonoverlapping and non-Japanese patients and detected losses of chromosomes 11p, 11q, 18q, 21q, and 22q as well as gains of chromosomes 7 and 12 (6). Moreover, losses of chromosomal arms 13q14 and 17p13, where the RB gene and the p53 gene exist, respectively, were not found in uremic parathyroid hyperplasias, indicating that inactivation of these tumor suppressor genes might occur uncommonly in this disease. Tahara et al. previously showed that losses were found frequently on chromosomes 1, 6, 9, 11, 13, and 15 as well as gains of chromosomes 16p and 19p in sporadic parathyroid adenomas, indicating that markedly different molecular pathogeneses exist for clonal outgrowth in severe uremic hyperparathyroidism vs. common sporadic parathyroid adenomas (29, 30). To clarify the roles of these chromosomal abnormalities in the pathogenesis of uremic parathyroid tumors, further investigations are necessary to identify candidate oncogenes and tumor suppressor genes existing in these loci.

In conclusion, somatic MEN1 gene mutation within the MEN1-coding region contributes to the pathogenesis of uremic parathyroid tumors, but its role in this disease appears to be very limited. As most parathyroid glands do not show LOH on 11q13, mutations in genes other than MEN1 have to be sought to explain the development of the majority of clonal parathyroid tumors in uremia.


   Acknowledgments
 
We thank Dr. Andrew Arnold for helpful discussion.


   Footnotes
 
1 This work was supported by a grant for Scientific Research (11770633, to H. T.) from the Ministry of Education, Science, and Culture, Japan. Back

Received November 30, 1999.

Revised May 31, 2000.

Revised July 11, 2000.

Accepted July 20, 2000.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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