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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 1 250-252
Copyright © 2000 by The Endocrine Society

Original Studies

Microsatellite Instability in Sporadic Parathyroid Adenoma1

Marta Sarquis, Eitan Friedman, Wolfanga L. Boson, Ricardo S. Gomez, Adalberto F. Dias and Luiz De Marco

Departments of Pharmacology (M.S., W.L.B., A.F.D., L.D.) and Pathology (R.S.G.), Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil; and The Susanne Levy Gertner Oncogenetics Unit (E.F.), Institute of Genetics, Chaim Sheba Medical Center, Tel Hashomer, 52621, Israel

Address correspondence and requests for reprints to: L. De Marco, M.D., Ph.D., Av. Antonio Carlos 6627, Belo Horizonte 31270-901, Brazil. E-mail: ldemarco{at}icb.ufmg.br


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Discussion
 References
 
Parathyroid adenomas are usually benign uniglandular tumors, and inactivation of several tumor suppressor genes, notably the MEN 1 gene, or activation of oncogenes have been implicated in the tumorigenesis. Genomic instability, indicative of the involvement of DNA mismatch repair genes, has not been previously described in parathyroid adenomas. A single large parathyroid adenoma was resected from an 8.5-yr-old Brazilian patient with no personal or family history of other endocrinopathies. Analysis of paired tumor-nontumor DNA using 23 microsatellite markers, located on chromosomes 1, 10, and 11 was carried out. Microsatellite instability was detected in nine markers (D1S191, D1S212, D1S413, D1S2848, RET, D11S901, D11S903, INSR, and INT2), whereas no allelic loss was detected with any of the analyzed markers. Immunohistochemical analysis of retinoblastoma protein expression revealed low levels of expression, but no histopathological signs of malignancy. We conclude that in this single, apparently sporadic parathyroid adenoma, DNA mismatch repair genes might be involved in parathyroid tumorigenesis.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Discussion
 References
 
PRIMARY hyperparathyroidism (HPT) is usually a sporadic disorder most commonly caused by uniglandular parathyroid adenoma (1). Multiglandular HPT may also be encountered in the context of rare hereditary syndromes, such as multiple endocrine neoplasia types 1 (MEN 1) and 2A (MEN 2A), HPT-jaw tumor syndrome, and familial isolated HPT (2, 3, 4, 5, 6). Uni- or multiglandular parathyroid adenomas are usually benign, monoclonal tumors (7), and genetic abnormalities within several genes have been detected in parathyroid neoplasms: allelic loss and inactivation of tumor suppressor genes, notably the MEN 1 (8, 9, 10, 11) and retinoblastoma genes (12), as well as other unidentified genes on chromosomes 1, 6, 9, and 15 (13), that have been shown in these tumors. Activation of oncogenes (e.g. PRAD) have also been demonstrated in a subset of these tumors (7, 14, 15). The involvement of DNA mismatch repair genes in the tumorigenic process is hallmarked by microsatellite instability (MIS). Microsatellites, also termed short tandem repeats, are sequence polymorphisms composed of repetitive di-, tri-, and tetranucleotide (most commonly CA repeats) that, because of their high informativeness, are useful for genetic mapping. Variations in the number of tandemly repeated nucleotides in a tumor but not in the normal adjacent tissue is called MIS. This phenomenon has been attributed to a mutator phenotype (16), an early event in colon carcinogenesis. MIS was initially demonstrated in colorectal cancer (17) but later was shown to be a feature of other neoplasms as well, including carcinoid tumors (18).

Here, we describe the presence of MIS in a large benign parathyroid adenoma detected in a child with early onset HPT.


   Material and Methods
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 Abstract
 Introduction
 Material and Methods
Results
 Discussion
 References
 
The patient’s parents gave informed consent to participate in this study, which was also approved by the University’s Ethics Committee.

Case report

An 8.5-yr-old girl was referred to Felício Rocho Hospital (Belo Horizonte, Brazil) for parathyroidectomy. Primary HPT was suspected at 7 yr of age because of repeated limb fractures and bone osteopenia, polyuria (3.5 liters/day), polydipsia, and nocturnal enuresis. Her parents were of Portuguese origin, healthy, nonconsanguineous, with two healthy younger siblings (4- and 3-yr-old) and no history of endocrinopathies in the family. Laboratory investigation revealed hypercalcemia (total plasma calcium, 13 mg/dL), hypophosphatemia (P = 2.4 mg/dL), high intact PTH [420 pg/mL (n = 12–72 pg/mL], hypercalciuria (urinary calcium, 209 mg/24 h; n, <120 mg/24 h), and deoxypyridinoline 92 nmol/mmol creatinine (n, <7 nmol/mmol creatinine). No clinical evidence of other endocrinopathies were present, and serum levels of gastrin, PRL, GH, insulin, TSH, ACTH, and cortisol were within normal limits. Calcium measurements in both parents and siblings were within normal limits. A single 3.0 x 0.8-cm upper right parathyroid adenoma was resected, with visual identification of the three other normal sized glands, but no biopsy was taken from these normal appearing glands. Histopathological evaluation, done by two independent pathologists, showed nests of oval cells with central regular nuclei and a clear amphophilic cytoplasm. The nests were supported by a delicate fibrous vascular stroma with occasional mitotic figures, and rare foci of infiltrating inflammatory cells were also present. No atypical mitoses, vascular, or capsule invasion were seen, supporting the diagnosis of a benign parathyroid adenoma and not carcinoma. Nontumorous tissue was carefully dissected out and tumor tissue, composed mostly (about 90%) of adenoma cells, were pooled and processed for DNA extraction.

Following surgery, normocalcemia, normal PTH, and resolution of all biochemical abnormalities ensued within 24 h (plasma calcium, 9.2 mg/dL; phosphorus, 3.8 mg/dL; and magnesium, 1.8 mg/dL). The patient was examined every 6 months for 2 years and then every year, after being discharged from the hospital in September 1995. When last seen (March 1999), 3.5 yr after surgery, she remains asymptomatic, her total plasma calcium was 9.0 mg/dL, phosphorus was 4.5 mg/dL, and high intact PTH was 45 pg/mL, all within normal limits.

PCR and microsatellite analyses

DNA from the parathyroid tumor and peripheral blood was extracted using standard protocols. The allelic patterns of 23 microsatellites, located on three different chromosomes, were investigated on paired tumor-nontumorous tissue. Samples were analyzed by the PCR amplification, followed by electrophoresis on 8% polyacrylamide gels. The microsatellites (Research Genetics, Inc., Huntsville, AL) used were D1S191, D1S202, D1S212, D1S222, D1S413, D1S422, D1S1415, D1S2823, D1S2848, D1S2877 (chromosome 1), ZNF, RET (chromosome 10), D11S1383, PYGM (AT), PYGM (CA), D11S415, D11S901, D11S903, D11S906, D1S4946, INSR, INT2, and HRAS (chromosome 11).

Samples were analyzed by PCR amplification. All PCR reactions were carried out in a final volume of 50 µl. Briefly, 4 µl extracted template tumor DNA, 5 µl 10x buffer [50 mM KCl, 10 mM Tris-HCl (pH 9.0), 0.1% Triton X-100, and 1.5 mM MgCl2], 15 pM of each up- and down-stream primers, 0.05 mM of each deoxynucleotide, and 0.3 U Taq DNA Polymerase (Perkin-Elmer Corp., Norwalk, CT). The cycling profile for all microsatellites was as follows: 94 C for 5 min (denaturing), followed by 45 cycles of denaturation at 94 C (1.5 min), annealing at 55 C (2.5 min), and extention at 72 C (1 min), with a final extension step of 5 min at 72 C. Following PCR, 10 µl of gel loading buffer was added to the sample, ran for 3–4 h at 160 V. Tumor and nontumor samples were analyzed in adjacent lanes and visualized by silver staining.

Immunohystochemistry

Tissue blocks were cut at 3 µm, mounted on glass plates, and subjected to the biotin-streptavidin-amplified system as described previously (19). The primary antibodies used were anti-p53 (Clone DO7; BioGenex Laboratories, Inc., San Ramon, CA), anti-MDM2 (Clone 1B10; Novocastra, Newcastle upon Tyne, UK), anti-cyclin A (Clone H-432; Santa Cruz Biotechnology, Inc., Santa Cruz, CA), anti-cyclin D (Clone R-124; Santa Cruz Biotechnology, Inc.), and anti-RB protein (Clone 84-B3–1; Novocastra). For the retinoblastoma protein, the catalyzed signal amplification system (DAKO Corp., Carpinteria, CA) was used as described by the manufacturer. One section of 5 µm was used for the conventional hematoxylin and eosin method. Six sporadic parathyroid adenomas and one oral squamous cell carcinoma with known immunoreactivity for p53, MDM2, cyclin A, cyclin D, and RB proteins served as controls. Negative controls included parallel sections from which either the primary or secondary antibodies were excluded. The immuno-expression of the antigens was semiquantitatively evaluated. The samples were classified as (-) negative staining, (+) less than 25% of positive cells, (++) between 26% and 50% of positive cells, and (+++) between 51% and 100% of positive stained cells.


   Results
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 Abstract
 Introduction
 Material and Methods
 Results
Discussion
 References
 
PCR analysis

No allelic loss was demonstrated in any of the loci analyzed. MIS was clearly detected in 9 of 23 markers located to the three different chromosomes analyzed (D11S901, D11S903, INSR, RET, INT2, D1S191, D1S212, D1S413, and D1S2848). Fig. 1Go shows representative patterns of MIS of markers D1S191, D1S2848, RET, and D11S901. No abnormalities were found in six markers of chromosome 11 (PYGM CA and AT, HRAS, D11S906, and D11S1383), one marker of chromosome 10 (ZNF), four markers of chromosome 1 (D1S222, D1S422, D1S1415, D1S2877, and D1S2823), and three markers were not informative (D1S202, D1S1415, and D11S4946).



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  		Figure 1. Microsatellite analysis of a parathyroid adenoma showing instability of four dinucleotide markers in three diferent chromosomal loci (chromosomes 1, 10, and 11). B, Constitutional DNA; T, tumor DNA. Dinucleotide marker D11S901 also shows two normal constitutional DNAs.

 
Immunohistochemistry

The tumor and the six control parathyroid adenomas showed similar immunostaining patterns for cyclins A and D, RB, p53, and MDM2 (data not shown). All were negative for p53 and showed a widespread positive MDM2 immuno-expression (++). Less than 10% of the tumor cells were positive for cyclin A, cyclin D, and RB protein (+). Nucleus and cytoplasmic immunoreactivity was observed for RB in all analyzed samples.


   Discussion
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 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
References
 
In this patient’s tumor, there are several unique features. The early age at onset probably can not be explained by any familial syndrome that includes primary HPT, as neither family history nor objective confirmation of any "familial" form of HPT was ascertained. Although the exact incidence is unknown, sporadic HPT is a rare event in children and young adolescents that causes significant morbidity if left untreated (20, 21, 22). Furthermore, resection of a single adenoma resulted in clinical and biochemical remission, another feature suggestive of a sporadic, uniglandular primary HPT. Analysis of tumor DNA compared to nontumorous tissue from the same individual showed no allelic loss at any investigated locus but, unexpectedly, strong evidence for MIS, as 9 of 20 informative markers showed mobility patterns compatible with MIS.

MIS implying DNA replication errors characterizes a proportion of familial and sporadic carcinomas. Alterations of microsatellites consisting of extra or missing copies of these sequences occur at relatively high frequencies in sporadic and hereditary colorectal adenocarcinomas, gastric and pancreatic cancers, esophageal adenocarcinomas, and at lower frequencies in endometrial, bladder, ovarian, and other carcinomas (17, 23, 24, 25, 26, 27). The utilization of chromosome 9p microsatellite polymorphisms to study parathyroid adenomas has been shown previously. Tahara et al. (28) used a large panel of microsatellites spanning all chromosomal arms to study allelic patterns in 25 sporadically occurring parathyroid adenomas and detected frequent allelic losses at various loci, but did not report MIS. These four tumors also had one or more chromosomal losses, suggesting multiple genetic lesions as a requirement for neoplastic transformation, but no MIS was found. Dotzenrath et al. (29) investigated 12 benign parathyroid adenomas and showed that heterozygosity was retained with markers on 13q14, 1q, and 1p, and no MIS was found. Analysis of markers from chromosomes 1p, 1q, 3q, 6q, 13q, 15q, and X in a total of 89 benign sporadic parathyroid adenomas by the same group (30) further extended their data, demonstrating allelic loss at various loci, but no MIS.

More recently, microsatellite polymorphic markers were also used to look for loss of heterozygosity in four patients from one kindred with familial isolated primary HPT (31), and allelic loss at chromosomes 9p21-p22 and 13q12.3-q32 were shown, but no MIS. The fact that among all these previously analyzed parathyroid tumors, either sporadic or familial, none displayed MIS, needs to be accounted for. It may indicate that MIS and, hence, the involvement of DNA mismatch repair genes in parathyroid tumorigenesis are related by an extremely early age of onset.

There were no apparent differences between the immunostaining pattern in this unique tumor and two other sporadic parathyroid adenomas when a number of antibodies were used. Altered immunostaining expression of RB protein in parathyroid tumors has been used to distinguish benign from malignant parathyroid disease (30, 32). Although the antibodies used by these authors to detect RB protein was different then the one used in our experiments, the immunohistochemical expression of this protein was similar in all three benign parathyroids, suggesting the benign nature of this parathyroid tumor. Another cell cycle regulator, p53 has been implicated in the pathogenesis of a small subset of parathyroid carcinomas (33), and our findings of normal p53 give support to the nonmalignancy of our studied lesion.

We conclude that genomic instability reflected by MIS may occasionally be detected in benign parathyroid adenoma, perhaps limited to the very young age group, and DNA mismatch repair genes should be included as putative, limited contributors to parathyroid tumorigenesis.


   Acknowledgments
 
We thank J. Andrade, M.D., and A. J. Barbosa, M.D., Ph.D., for independent histopathological/immunohistochemical analyses and Ms. Adriana R. Moreira for technical assistance.


   Footnotes
 
1 Supported by grants from Pronex and FAPEMIG (Brazil) to L.D. and from Tel Aviv University (Israel) to E.F. Back

Received August 12, 1999.

Revised October 18, 1999.

Accepted October 21, 1999.


   References
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 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 

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