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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 3 1248-1251
Copyright © 2003 by The Endocrine Society

Analysis of Microsatellite Instability in Sporadic Parathyroid Adenomas

Sanjay M. Mallya, James J. Gallagher and Andrew Arnold

Center for Molecular Medicine and Division of Endocrinology and Metabolism, University of Connecticut School of Medicine (S.M.M., J.J.G., A.A.), and Department of Oral Diagnosis, University of Connecticut School of Dental Medicine (S.M.M.), Farmington, Connecticut 06030

Address all correspondence and requests for reprints to: Andrew Arnold, M.D., Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030-3101. E-mail: aarnold{at}nso2.uchc.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Microsatellite instability (MSI) is the form of genomic instability associated with defective DNA mismatch repair (MMR) in human tumorigenesis. Recent reports have suggested a role for MSI in the pathogenesis of sporadic parathyroid adenomas. However, because of their small sample sizes and/or lack of systematic analysis of genome-wide MSI, these studies have not provided conclusive evidence that MMR defects are a common occurrence in parathyroid neoplasia. To further investigate whether MSI plays an important role in parathyroid tumorigenesis, we analyzed 49 sporadic parathyroid adenomas for MSI using a panel of 5 microsatellite DNA markers that has been recommended for sensitive detection of MSI by the NCI Workshop and validated in other tumor types. These microsatellite loci were amplified by PCR using fluorescent-labeled primers from the 49 samples of template tumor DNA and matching normal DNA isolated from the same patients’ peripheral blood leukocytes. None of the 49 tumors showed evidence of MSI at any of the analyzed loci of the NCI marker panel. These observations strongly suggest that defective DNA MMR plays a minor role, if any, in the pathogenesis of sporadic parathyroid adenomas.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PARATHYROID ADENOMAS ARE benign neoplasms that are the most common cause of primary hyperparathyroidism. These neoplasms are monoclonal (1), indicating that they result from acquired damage in a set of key genes within a parathyroid cell, conferring a selective advantage upon that cell and its progeny. Currently, two such genes are established contributors to sporadic parathyroid adenomas, the cyclin D1 oncogene (1, 2, 3, 4, 5, 6, 7) and the MEN1 tumor suppressor gene (8, 9, 10, 11, 12, 13). Evidence also exists for other, still unidentified, parathyroid oncogenes and tumor suppressor genes (1, 14, 15, 16, 17). It has been suggested that the slow growth rates of parathyroid adenomas may be insufficient to account for generation, at typical mutation rates, of the observed number of clonal DNA alterations detected in these neoplasms (18). A possible explanation could be the presence of genomic instability in these tumors. One form of genomic instability is microsatellite instability (MSI), caused by inactivation of the DNA mismatch repair (MMR) system, which normally corrects base pair mismatches arising during DNA replication. Microsatellites, composed of multiple 1- to 5-bp units, are found throughout the genome and are prone to strand slippage and replication errors. Thus, a state of genome-wide instability at microsatellite loci is an indicator of defective MMR. Inactivation of MMR is the underlying basis for tumorigenesis in patients with hereditary nonpolyposis colorectal carcinoma. Defects in MMR are also observed in a subset of sporadic colorectal carcinomas and other tumor types, including tumors of the endometrium, ovary, stomach, pancreas, prostate, and kidney (19, 20, 21, 22).

Recent studies have suggested that MSI may play a role in the pathogenesis of sporadic parathyroid adenomas (23, 24, 25). However, because of their small sample sizes and/or lack of systematic analysis of genome-wide MSI, these studies have not provided conclusive evidence that MMR defects are a common occurrence in parathyroid neoplasia. To further investigate whether MSI plays an important role in parathyroid tumorigenesis, we analyzed a large group of sporadic parathyroid adenomas for signs of MSI, using a panel of five microsatellite markers recommended for this purpose by the NCI Workshop on Microsatellite Instability (26).


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

Parathyroid adenoma tissue samples were obtained from 49 unselected patients (34 females and 15 males), with no history or manifestations of familial hyperparathyroidism or a multiple endocrine neoplasia syndrome, undergoing parathyroidectomy for treatment of primary hyperparathyroidism. Additional demographic and clinical information was available for 46 patients. The mean age at the time of surgery was 54 yr (range, 10–82 yr). Although the age at presentation was quite typical for the large majority of patients, it was noted that 4 patients presented at an unusually young age (<20 yr), albeit with no history of familial hyperparathyroidism, thus broadening the clinicopathological spectrum in which MSI might be uncovered in this series. The mean weight (±SD) of the excised glands was 2.02 ± 2.47 g. All patients were surgically and pathologically demonstrated to have single gland disease with no malignant features and responded to removal of the lesion with reversal of hypercalcemia. After surgical removal, tumor tissue was carefully dissected, frozen in liquid nitrogen, and stored at -80 C before extraction of DNA by standard methods (27). DNA from patients’ paired venous blood samples was similarly extracted. All tumor and blood samples were obtained in accordance with institutional review board oversight.

Amplification of microsatellite loci and analyses of microsatellite instability

For each sample of tumor DNA, 5 microsatellite loci (D2S123, D5S346, D17S250, BAT25, and BAT26; Table 1Go) were amplified by PCR. This panel of markers has been recommended by the NCI for reliable and sensitive detection of MSI in colorectal cancers and has been validated for other tumor types, such as ovarian carcinomas (28). Fluorescent-labeled PCR primers corresponding to these loci were synthesized on a DNA synthesizer (Sigma, Genosys, The Woodlands, TX). DNA extracted from the tumor samples and leukocytes were amplified in 20-µl PCR reactions containing 0.2 mmol/liter deoxy-NTPs, 1 U AmpliTaq Gold (PE Applied Biosystems, Foster City, CA), 2 µl of 10x AmpliTaq Gold PCR buffer, 1 mmol/liter magnesium chloride, and 20 pmol/liter forward and reverse primer pairs. PCR reactions were performed on a Hybaid thermocycler (ThermoHybaid, Franklin, MA) using the following conditions: initial denaturation at 95 C for 5 min, followed by 30 cycles of denaturation at 94 C for 1 min, annealing at 50 C for 45 sec, and extension at 72 C for 60 sec, and a final extension step at 72 C for 30 min. For each case, tumor DNA and paired normal DNA was amplified in 3 separate PCR reactions, containing PCR primers D1S123 and BAT26, D5S346 and D17S250, and BAT25. After amplification, all PCR products were pooled and separated by electrophoresis on 5% polyacrylamide gels in an ABI 377 sequencer (PE Applied Biosystems). Data were analyzed using Genescan and Genotyper software (PE Applied Biosystems). MSI was scored as tumor-specific alterations in the size of microsatellite repeat regions (appearance of novel length allelic peaks or shift of peaks). In accordance with the NCI guidelines, the loss of one allelic peak and the absence of a novel allelic peak were scored as loss of heterozygosity and MSI negative. DNA from an MSI-positive colon carcinoma (provided by Dr. Manuel Perucho, The Burnham Institute, La Jolla, CA) served as a positive control. Two authors (S.M. and J.G.) analyzed the results independently. The NCI criteria were used to classify tumors as high frequency MSI (MSI-H; instability at 2 or more markers), low frequency MSI (MSI-L; instability at only 1 marker), and microsatellite stable (MSS; no instability detected at any of the 5 markers). To rule out artifacts inherent to the PCR process, i.e. due to polymerase slippage or to migration errors in the gel, instability at a marker locus was scored only when microsatellite alterations could be reproduced in repeat PCR reactions.


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  		Table 1. Microsatellite markers analyzed

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We analyzed the NCI panel of microsatellite loci in 49 parathyroid adenomas and paired constitutional DNA samples for signs of microsatellite instability. All 5 microsatellite loci were reliably amplified from tumor and normal DNA in 46 cases. In the remaining 3 cases, the BAT25 locus could not be amplified in the tumor DNA, but was amplified from normal DNA. None of the tumors showed signs of MSI at any of the microsatellite loci analyzed (Table 2Go and Fig. 1Go). DNA from a known MSI-positive colon carcinoma showed tumor-specific alterations in peak size, or the appearance of novel length alleles (Fig. 1Go), as expected.


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  		Table 2. Frequency of microsatellite instability and loss of heterozygosity in sporadic parathyroid adenomas

 


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  		Figure 1. Amplification of the five microsatellite loci in tumor DNA and paired normal DNA. Peaks representing amplified microsatellite loci are shown (left panel, colon carcinoma; right panel, parathyroid adenoma; N, constitutional DNA; T, tumor DNA). Amplification of DNA from an MSI-positive colon carcinoma DNA shows tumor-specific alterations in peak sizes (D5S346, Bat-25, and Bat-26) and the presence of novel length alleles (D2S123 and D17S250). In contrast, no signs of MSI are noted in the parathyroid tumor.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study we systematically analyzed a large panel of sporadic parathyroid adenomas for signs of MSI. This approach has several strengths. First, we used a panel of microsatellite markers, recommended by the NCI Workshop on Microsatellite Instability (26). Initially developed for colorectal cancers, these markers have been validated for detection of MSI in other tumor types, such as ovarian carcinomas (28). The panel includes three dinucleotide and two mononucleotide repeat markers scattered through the genome. Inclusion of the mononucleotide repeats (BAT25 and BAT26) is particularly important, as these markers are highly sensitive for the detection of MSI in colorectal carcinomas (29) as well as in other tumor types, including tumors of the breast, brain, stomach, prostate, esophagus, thyroid, endometrium, and cervix (30). A second advantage of this approach is the use of fluorescent-labeled primers and the use of laser scanning for PCR product detection, which standardize migration and minimize false positives that may result from migration errors. The third strength is the use of stringent criteria for scoring instability at marker loci. Because of their repetitive structure, microsatellites are prone to errors from polymerase slippage. Such errors may also occur during the PCR amplification process. Therefore, to eliminate false positives due to PCR-based artifacts, instability was scored only when tumor-specific microsatellite alterations could be reliably reproduced on subsequent repeat PCR reactions. Finally, we used a large sample of tumors to better estimate the fraction of sporadic parathyroid tumors that might exhibit MSI. Thus, this is the first study to systematically evaluate the contribution of MSI in parathyroid tumorigenesis.

Given that MSI was not detected in any of the 49 sporadic parathyroid adenomas analyzed, our results suggest that MSI is, at best, a rare feature in parathyroid adenomas and is unlikely to play an important role in the pathogenesis of these tumors. In contrast, a previous study by Koshiishi et al. (24) reported that MSI was observed in 43% of parathyroid adenomas. This study examined 17 microsatellite loci in 14 parathyroid adenomas and found that 6 tumors showed MSI at 1 or more loci (24). All 17 markers were dinucleotide repeats, and the lack of inclusion of mononucleotide markers, which are more sensitive for the detection of true MSI (29, 30), is a limitation of that study. Furthermore, when the data reported by Koshiishi et al. (24) are reanalyzed with criteria developed at the NCI workshop (26), classifying tumors as MSI-H (when >=30–40% of marker loci examined show signs of instability), MSI-L (instability at <=30–40% of marker loci), or MSS (no instability at any of the markers examined), only 1 of the 14 tumors fits the category of MSI-H. Thus, even in their sample of tumors, MSI-H is an infrequent finding in parathyroid adenomas. The other 5 ostensibly MSI-positive tumors reported by Koshiishi et al. (24) would be classified as MSI-L. However, the existence of MSI-L tumors as a meaningful separate category has recently been challenged, because unlike MSI-H tumors, MSI-L tumors have no phenotypic traits that distinguish them from MSS tumors (31). Interestingly, a recent study of colorectal cancers shows that all cancers demonstrate some degree of MSI if sufficient microsatellites were typed, and the greater the number of markers used, the greater the chances of classifying a tumor as MSI-L (32). This phenomenon was attributed to random microsatellite slippage and the fact that the clonal nature of tumors would make this slippage detectable. These findings strengthen the argument that MSI-L tumors may not be a category distinct from MSS tumors and thus may not reflect a true state of MMR deficiency.

Because no studies have specifically validated the use of the NCI-recommended marker panel for detection of MSI in parathyroid tumors, it is certainly possible that the inclusion of additional markers in our panel might have increased the number of tumors that demonstrated MSI at one or more loci. However, as discussed above, the inclusion of two mononucleotide repeats (BAT25 and BAT26) that are highly sensitive for detection of MSI-H in a variety of human tumors (29, 30) makes it unlikely that our methodology failed to detect parathyroid tumors with MSI-H. Further, although we might have classified certain tumors as MSI-L instead of MSS had we used a significantly larger panel of markers, the biological distinction between MSI-L and MSS categories is dubious as discussed above. Finally, two other reports of MSI in parathyroid tumors exist. One group found MSI in a single case report of a parathyroid adenoma from an 8-yr-old patient (23). The researchers suggested that MSI might be a feature of parathyroid adenomas occurring in the young age group (23). Interestingly, our series included four adenomas from young patients, between 10–20 yr of age, and none exhibited signs of MSI. Another group reported MSI in one of four hyperplastic parathyroid glands removed from a patient with tertiary hyperparathyroidism undergoing phosphate therapy for acquired hypophosphatemic osteomalacia (25); the relevance of this findings to the pathogenesis of typical sporadic parathyroid adenomas is unclear. In summary, our observations indicate that MSI plays a minor role, if any, in the pathogenesis of common sporadic parathyroid adenomas. As such, an increased mutational rate subsequent to defective mismatch repair is unlikely to be the underlying basis of clonal DNA alterations detected in parathyroid adenomas.


   Acknowledgments
 
We thank Dr. Manuel Perucho for providing us with DNA from an MSI-positive colon tumor.


   Footnotes
 
This work was supported in part by Grant DE14773 from the National Institute of Dental and Craniofacial Research (to S.M.), the John G. Haddad, Jr. Award from The Paget Foundation (to A.A. and S.M.), and the Murray-Heilig Fund in Molecular Medicine (to A.A.).

Abbreviations: MMR, Mismatch repair; MSI, microsatellite instability; MSI-H, high frequency microsatellite instability; MSI-L, low frequency microsatellite instability; MSS, microsatellite stable.

Received September 16, 2002.

Accepted December 4, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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