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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2960-2963
Copyright © 1998 by The Endocrine Society

Original Studies

Parathyroid MEN1 Gene Mutations in Relation to Clinical Characteristics of Nonfamilial Primary Hyperparathyroidism1

Tobias Carling, Pamela Correa, Ola Hessman, Jakob Hedberg, Britt Skogseid, Daniel Lindberg, Jonas Rastad, Gunnar Westin and Göran Åkerström

Department of Surgery, Endocrine Unit, and Department of Internal Medicine (B.S.), Uppsala University Hospital, 751 85 Uppsala, Sweden

Address all correspondence and requests for reprints to: Tobias Carling, Ph.D., Department of Surgery, Endocrine Unit, Uppsala University Hospital, S-751 85 Uppsala, Sweden. E-mail: tobias.carling{at}kirurgi.uu.se


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Biochemical signs and severity of symptoms of primary hyperparathyroidism (pHPT) differ among patients, and little is known of any coupling of clinical characteristics of nonfamilial pHPT to genetic abnormalities in the parathyroid tumors. Mutations in the recently identified MEN1 gene at chromosome 11q13 have been found in parathyroid tumors of nonfamilial pHPT. Using microsatellite analysis for loss of heterozygosity (LOH) at 11q13 and DNA sequencing of coding exons, the MEN1 gene was studied in 49 parathyroid lesions of patients with divergent symptoms, operative findings, histopathological diagnosis, and biochemical signs of nonfamilial pHPT. Allelic loss at 11q13 was detected in 13 tumors, and 6 of them demonstrated previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of the detected mutations would most likely result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and biochemical characteristics of HPT were apparently unrelated to the presence or absence of LOH and the MEN1 gene mutations. However, the demonstration of LOH at 11q13 and MEN1 gene mutations in small parathyroid adenomas of patients with slight hypercalcemia and normal serum PTH levels suggest that altered MEN1 gene function may also be important for the development of mild sporadic pHPT.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PREVALENCE of nonfamilial primary hyperparathyroidism (HPT) rises with age for both sexes, and health-screening examinations have suggested a 2–3% prevalence in Swedish postmenopausal females (1, 2). The disease exhibits variable clinical presentation, and biochemically mild forms with little risk of progression over time have been substantiated (1). The pathogenesis of increased cell proliferation and PTH release of primary HPT is largely unknown. Polymorphic alleles in the vitamin D receptor gene comprise a recently identified risk factor in postmenopausal females, and heterogeneous pathogenesis of HPT in different patient subgroups might be contemplated (3, 4, 5, 6). Primary HPT may also be part of the familial multiple endocrine neoplasia type 1 (MEN-1) syndrome (7), which has been coupled to a variety of mutations in the recently identified MEN1 tumor suppressor gene at chromosome 11q13 (8, 9, 10, 11, 12, 13).

Loss of heterozygosity (LOH) at the MEN-1 locus on chromosome 11q13 has been demonstrated in approximately 25–40% of sporadic parathyroid tumors (10, 11, 14, 15). Recent analysis of the MEN1 gene demonstrated mutations in 7 of 33 such tumors (14), which comprised point mutations and deletions/insertions confined to those with LOH at 11q13. As the MEN1 gene may participate in the parathyroid tumorigenesis of nonfamilial primary HPT, any coupling of the genetic changes to clinical characteristics of the disorder becomes an important concern. The present study investigates genetic abnormalities of the MEN1 gene in relation to symptoms and biochemical signs of nonfamilial primary HPT, with emphasis on postmenopausal females exhibiting a biochemically mild and overtly asymptomatic disorder.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and biochemistry

Forty-nine patients (43 women and 6 men) with operatively verified, nonfamilial primary HPT were included into the study. Twenty-four postmenopausal females (mean age, 70.3 yr) were recruited by population-based HPT screening among women, 55–75 yr old, living in Uppsala County (2). This screening was designed especially to unveil asymptomatic HPT accompanied by normal and intermittently elevated serum calcium values. The patients underwent parathyroid operation to explore its potential influences compared to those of other treatment strategies. Another 25 patients (19 females and 6 men; mean age, 66.7 yr) comprised routine referrals for parathyroid surgery. These patients were selected to include those with greater extents of the hypercalcemia and parathyroid enlargement, such as parathyroid cancer and water-clear cell hyperplasia. The presence or absence of classical symptoms of HPT were determined by routine interview and defined as previously described (16).

HPT was due to single adenoma (n = 37), parathyroid cancer (n = 2), or hyperplasia (n = 10) upon conventional microscopic analysis of the operative specimens (17). Parathyroid hyperplasia of the chief cell (n = 9) or water-clear cell type (n = 1) was defined as a multiglandular parathyroid enlargement. None of the patients demonstrated a history of familial hypercalcemia or clinical and biochemical signs of MEN syndromes (7). Blood was collected after an overnight fast, and serum (s-) calcium, corrected for s-albumin (reference range, 2.20–2.60 mmol/L), and intact s-PTH (Nichols Institute, San Juan Capistrano, CA; reference range, 12–55 ng/L) were determined preoperatively. All patients had postoperatively reversed hypercalcemia during follow-up for at least 9 months.

LOH

Leukocyte DNA was extracted according to standard procedures. The parathyroid tissue intended for DNA preparation was intraoperatively snap-frozen in liquid nitrogen and stored at -70 C. DNA extraction from cryosections (12 µm) of parathyroid tissue or parathyroid biopsies encompassed digestion with proteinase K and precipitation in saturated ammonium acetate and ethanol. Macroscopically identified rims of normal parathyroid tissue of adenomas were excised before DNA preparation, and the largest gland was chosen for genetic investigations in the cases of parathyroid hyperplasia. All parathyroid lesions were subjected to LOH screening using three microsatellite markers at chromosome 11q13 [PYGM(CA), INT-2, and D11S906] (9, 18). PCR (10 µL) was performed with 2 pmol 32P end-labeled forward primer, 2 pmol reverse primer, 20 ng genomic DNA, 0.2 U Taq polymerase, 1 x PCR buffer, 1.5 mmol/L MgCl2, and 100 µmol/L deoxy-NTPs. The PCR conditions used an initial denaturation at 95 C, followed by 27 cycles at 95 C for 30 s, 55–62 C for 30 s, and 72 C for 30 s, with a final extension at 72 C for 7 min. PCR products were mixed with formamide gel loading solution, heat denatured, run on a denaturing 4.5% polyacrylamide sequencing gel, and visualized on a PhosphorImager (Molecular Dynamics, Sunnyvale, CA). Complete loss or more than 50% reduction of 1 of the 2 alleles present in heterozygous individuals was considered to represent LOH (19).

Mutational analysis

Exons 2–10 of the MEN1 gene were sequenced in the 13 parathyroid tumors with LOH at chromosome 11q13 as well as 4 other parathyroid tumors, including 2 carcinomas and 2 adenomas. The exons were amplified using primers 1F-2R, 3F-4R, 5F-6R, 7F-7R, 8F-9R, 10F-10R, 11F-11R, 12F-12R, 13F-14R, and 15F-15R (13). Briefly, PCR was performed using 200 ng genomic DNA and 25 pmol of each primer, and approximately 60 ng of the PCR product underwent sequencing of both DNA strands using the Applied Biosystems PRISM dye terminator cycle sequencing ready reaction kit (Perkin-Elmer, Applied Biosystems, Foster City, CA). When an abnormal sequence was detected, the corresponding leukocyte DNA was sequenced, and the tumor DNA was resequenced.

Statistical analysis

Student’s unpaired two-tailed t test and the {chi}2 test were used for statistical evaluation, with P < 0.05 considered significant. All results are expressed as the mean ± SEM, except for tumor weight, which is presented as the geometrical mean ± SE of the geometrical mean.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
As expected, HPT patients from the population-based screening displayed lower levels of s-calcium and s-PTH as well as smaller parathyroid lesions than those recruited in the clinical routine (P < 0.001; Table 1Go). Moreover, the patients detected by screening less often substantiated the presence of classical symptoms of HPT (P < 0.0001). All individuals were heterozygous and informative for at least 1 of the microsatellites [PYGM(CA), INT-2, or D11S906] at chromosome 11q13. A total of 13 of 49 (27%) parathyroid lesions demonstrated LOH, and 8 of these had allelic loss at more than 1 locus. LOH at 11q13 was more prevalent in patients with parathyroid adenomas (12 of 37; 32%) than in those with hyperplasia (1 of 10; 10%), and loss could not be detected in parathyroid carcinoma or water-clear cell hyperplasia. Unequivocal differences in clinical indices of HPT, such as age, s-calcium, s-PTH, or glandular weight, could not be detected between patients with and without LOH at 11q13 (Table 1Go). Ten of the 13 patients exhibiting allelic loss were recruited from the population-based screening for HPT. Five of them had normal s-PTH levels (range, 40–54 ng/L), and 4 had parathyroid adenomas weighing less than 300 mg.


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  		Table 1. Clinical characteristics, LOH at 11q13, and MEN1 gene mutations of the patients with nonfamilial primary HPT recruited by screening and in the clinical routine

 
DNA from the parathyroid lesions of all 13 patients demonstrating allelic loss at 11q13 and from another 4 parathyroid adenomas and carcinomas underwent automated sequencing of exons 2–10 of the MEN1 gene (Table 2Go). The MEN1 gene mutations were restricted to the specimens with LOH at 11q13 and are presented according to standard nomenclature (20). Two missense mutations (L152W and H139D) with predicted alteration of the amino acid sequence and 4 frameshift deletion mutations (405del1, 1313del19, 258del4, and 44del16) were found in 6 patients (46%) exhibiting LOH at 11q13 (Fig. 1Go). The aberrant tumor DNA sequence differed from the patient’s germline sequence and the recently published MEN1 sequence (9, 13). Four of the 6 mutations were found in the relatively large exon 2, and the remaining mutations were found in exons 3 and 9, respectively. The MEN1 gene mutations occurred in patients with discrepant s-calcium and intact s-PTH values and highly variable weights of the abnormal parathyroid tissue (Table 1Go). Overall, these variables mirrored those of the underlying HPT patient group. Four of the mutations occurred in the patients detected by population-based screening. Three of them had mild, asymptomatic primary HPT in conjunction with a parathyroid adenoma weight below 300 mg, s-calcium less than 2.75 mmol/L, and intact s-PTH in the normal range (Table 2Go). The largest parathyroid gland of 1 patient with parathyroid hyperplasia had a MEN1 gene mutation (L152W), and DNA from the other glands could not be obtained.


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  		Table 2. Clinical data of the six HPT patients with MEN1 gene mutations and loss of heterozygosity at 11q13 in the parathyroid lesions

 


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  		Figure 1. MEN1 gene mutations in two patients with nonfamilial parathyroid adenoma (A; 290 mg) and hyperplasia (B; 1350 mg). A 16-bp deletion (44del16) in exon 2 (A) and a C to T transition (L152W) changing a leucine to tryptophan in exon 3 (B) were detected by automated sequence analysis of the tumor DNA, but not in the corresponding germline DNA. Contaminating germline DNA was detected in the tumor DNA preparation in A. See Table 2Go for additional patient information.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Most parathyroid adenomas and some parathyroid hyperplasias represent monoclonality (21, 22), although it has been proposed that the neoplastic growth may be preceded by true polyclonal parathyroid hyperplasia (23). Influences of vitamin D receptor alleles may be important in the formation of parathyroid neoplasia (3, 4, 5, 6) and seem to contribute to the development of mild primary HPT mainly in postmenopausal females. In contrast, the parathyroid oncogene PRAD1 and the tumor suppressor gene Rb have been suggested to be involved in large parathyroid adenomas and carcinomas from symptomatic HPT patients with high levels of s-calcium and s-PTH (23, 24, 25, 26). Divergent pathogenesis consequently could exist in clinically discrepant subgroups of nonfamilial pHPT. In addition, LOH at other chromosomal loci than 11q13, such as 1p, 6q, 11p, 11q, and 15q, suggests that a number of genes may contribute to the parathyroid tumorigenesis (15, 19, 27).

Allelic loss at the MEN1 gene locus has previously been demonstrated in approximately 25–40% of nonfamilial parathyroid tumors (10, 11, 14, 15, 27). Using three highly polymorphic microsatellites within the 11q13 region, LOH was detected in 13 (27%) of the currently investigated lesions. This material was selected to include a variety of clinical subgroups of HPT. The somewhat low incidence of allelic loss is possibly related to overrepresentation of parathyroid hyperplasia (n = 10) and carcinoma (n = 2), in which LOH at 11q13 seems to be rare. The unusual number of small parathyroid lesions in the present material possibly had a lesser influence in this respect, as LOH at the MEN1 gene locus has been claimed to be unrelated to the tumor size (11).

MEN1 gene mutations were found only in parathyroid tumors demonstrating LOH at 11q13, and the occurrence of mutations in 46% of such lesions is consistent with the findings of a previous study (14). Apart from known MEN1 gene polymorphisms (9, 12, 13), we detected two missense mutations (L152W and H139D) leading to predicted alterations in the amino acid sequence and four frameshift deletion mutations (405del1, 1313del19, 258del4, and 44del16) in the tumor DNA. None of these were present in the corresponding germline DNA. The H139D mutation has previously been detected in an MEN-1 kindred (12), but the others have not been demonstrated in these patients or in those with nonfamilial parathyroid lesions (9, 12, 13, 14, 28). This finding further emphasizes the heterogeneity of MEN1 gene mutations. The effect of the mutations described herein on the MEN1 gene function remains to be clarified, but the presence of large deletions indicates loss of function of the menin protein in these lesions.

Divergent clinical characteristics of HPT were recorded in the patients with LOH at 11q13 and in those with MEN1 gene mutations in their parathyroid lesions. Such genetic abnormalities were found in a substantial proportion of patients recruited by population-based HPT screening. This screening was deliberately set to detect even mild forms of primary HPT (2, 29) and, therefore, provided a unique opportunity to study the MEN1 gene in small parathyroid neoplasias accompanied by normal to slightly elevated s-calcium values, normal s-PTH, and absence of clinically overt symptoms of the disorder. The presence of MEN1 gene mutations in parathyroid adenomas of such a patient group is interesting and suggests that the loss of function of this tumor suppressor gene is not necessarily associated with excessively increased parathyroid cell proliferation.


   Acknowledgments
 
Primers for LOH were generously provided by the Department of Clinical Genetics at the Uppsala University Hospital.


   Footnotes
 
1 This work was supported by the Swedish Medical Research Council, the Swedish Cancer Society, and the Swedish Society for Medical Research. Back

Received January 8, 1998.

Revised March 25, 1998.

Accepted April 6, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals