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Alternative Genetic Pathways in Parathyroid Tumorigenesis¹

Departments of Molecular Medicine Endocrine Tumor Unit (F.F., S.K., B.T.T., F.K.W., C.L.), Clinical Pathology (A.H.), and Surgery (L.O.F., K.S.) Karolinska Hospital, SE-171 76 Stockholm, Sweden; Molecular Genetics Unit, Kolling Institute of Medical Research, Royal North Shore Hospital (T.D.), Sydney 0265, Australia; the Department of Surgery, Huddinge Hospital (M.E.), SE-14186 Huddinge, Sweden; the Department of Clinical Biochemistry, King’s College School of Medicine and Dentistry (W.S.W.), London SE59PJ, United Kingdom; and the Department of Surgery, University of Michigan Hospital (N.W.T.), 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, SE-171 76 Stockholm, Sweden.

	Abstract

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In this study 44 parathyroid tumors from 26 sporadic cases, 10 cases previously given irradiation to the neck, and 8 familial cases were screened for sequence copy number alterations by comparative genomic hybridization. In the sporadic adenomas, commonly occurring minimal regions of loss could be defined to chromosome 11 (38%), 15q15-qter (27%), and 1p34-pter (19%), whereas gains preferentially involved 19p13.2-pter (15%) and 7pter-qter (12%). Multiple aberrations were found in sporadic tumors with a somatic mutation and/or loss of heterozygosity of the MEN1 gene. The irradiation-associated tumors also showed multiple comparative genomic hybridization alterations and frequent losses of 11q (50%), and subsequent analysis of the MEN1 gene demonstrated mutations in 4 of 8 cases (50%). The adenomas from familial cases showed few alterations, and in 3 of these tumors a gain of 19p13.2-pter was seen as the only aberration. In this study numerical copy number alterations were frequently detected in sporadic and irradiation-associated parathyroid adenomas, although these tumors are benign. The majority of these alterations were found in tumors with confirmed involvement of the MEN1 gene locus in agreement with a role of the MEN1 gene in genomic stability. Furthermore, the frequent occurrence of MEN1 mutations (50%) in irradiation-associated parathyroid tumors suggests that inactivation of the MEN1 gene is an important genetic alteration involved in the development of parathyroid tumors in postirradiation patients.

	Introduction

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HYPERPARATHYROIDISM (HPT) is one of the most common endocrinopathies. Among women over 50 yr of age the prevalence is as high as 1–2%. HPT occurs in both sporadic and familial forms; the familial is associated with syndromes such as multiple endocrine neoplasia type 1 (MEN 1), familial hypocalciuric hypercalcemia (FHH), the hyperparathyroidism-jaw-tumor syndrome (HPT-JT/HRPT2), and familial isolated hyperparathyroidism (FIHP). Sporadic primary hyperparathyroidism (PHPT) has long been considered idiopathic, because the etiology is largely unknown. In addition to age and sex, external irradiation to the neck is regarded as a significant risk factor. The malignant form of hyperparathyroidism, parathyroid cancer, is very rare, especially when considering the high incidence of benign parathyroid neoplasias. The genes responsible for MEN 1 and FHH have been identified, and we have recently shown that FIHP can occur as a genetic variant of MEN 1 or be linked to the 1q region for HPT-JT or HRPT2, which is yet to be cloned (1, 2).

During the last decade several genetic mechanisms involved in parathyroid tumorigenesis have been elucidated. These include deletions of chromosomal regions to which familial syndromes are mapped. The 11q13 region, which harbors the MEN1 tumor suppressor gene (3, 4), is deleted in a third of sporadic PHPT (5) (Dwight. T., et al., unpublished observations), and in half of these cases a somatic MEN1 mutation has been demonstrated (6, 7, 8) (Dwight, T., et al., unpublished observations). Allelic losses of the HRPT2 region in 1q32-q41 (9) occurs repeatedly in parathyroid tumors from linked FIHP families (2), but are infrequent in HPT-JT and sporadic HPT (9, 10, 11). Results from loss of heterozygosity (LOH) and comparative genomic hybridization (CGH) studies in sporadic PHPT have demonstrated frequent deletions of chromosomes 1p, 6q, 9p, 11q, 13q, 15q, and X as well as gain of chromosomes 16p and 19p (10, 12). In the present work, we have furthered the CGH studies by analyzing sporadic tumors with and without involvement of the MEN1 gene and, in addition, specimens from irradiation-associated as well as familial parathyroid tumors.

	Materials and Methods

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Patients and tumor specimens

High molecular weight DNA was prepared from fresh frozen tumor tissues using standard methods. A total of 44 tumors from 43 patients with different types of hyperparathyroidism were studied, and the clinical data are detailed for each case in Tables 1-3. The 26 sporadic ordinary adenomas had previously been characterized for MEN1 gene alterations by LOH and mutation analysis (Table 1) as previously reported (7). Ten adenomas were from patients who had previously undergone irradiation treatment to the neck (Table 2). Eight other adenomas were from patients with a familial predisposition for HPT other than MEN 1 (Table 3), 2 of which were from the same FIHP family with confirmed linkage to 1q (2). By histopathological investigation all tumor samples included in this study were shown to contain a minimum of 70% tumor cells. Informed consent was obtained from all patients, and the study was approved by the ethics committee of the Karolinska Hospital.

CGH was performed as previously described (13). Briefly, tumor DNA samples were labeled with fluorescein isothiocyanate-deoxy-UTP (DuPont, Boston, MA) by nick translation, and normal reference DNA was labeled with Texas Red (Vysis, Inc., Downers Grove, IL). Tumor and reference DNA were mixed with unlabeled Cot-1 DNA (Life Technologies, Inc., Gaithersburg, MD), denatured, and applied onto slides with denatured metaphases of normal lymphocytes (Vysis, Inc.). After hybridization at 37 C for 72 h, the slides were washed in 0.4 x SSC (standard saline citrate)-0.3% Nonidet P-40 at 74 C for 2 min and in 2 x SSC-0.1% Nonidet P-40 at room temperature for 1 min. After air-drying, the slides were counterstained with 4,6-diamino-2-phenylindole (Vysis, Inc.). Two control experiments were also performed, including normal DNA hybridized against normal metaphases and DNA from a previously characterized breast cancer cell line (MPE 600, Vysis, Inc.) hybridized against normal metaphases from a reference woman.

Digital image analysis

Six to 10 three-color digital images (4,6-diamino-z-phenylindol, fluorescein isothiocyanate, and Texas Red fluorescence) were collected from each hybridization using a Axioplan 2 (Carl Zeiss Jena GmbH, Jena, Germany) epifluorescence microscope and Sensys (Photometrics) charge-coupled device camera interfaced to a IPLab Spectrum 10 workstation (Signal Analytics Corp., Vienna, VA). Relative DNA sequence copy number changes were detected by analyzing the hybridization intensities of tumor and normal DNAs along the length of all chromosomes in each metaphase spread. The absolute fluorescence intensities were normalized so that the average green to red ratio of all chromosomes in each metaphase was 1.0. The final results were plotted as a series of green to red ratio profiles and corresponding SD for each human chromosome from p-telomere to q-telomere. At least 12 ratio profiles (6 separate metaphases) were averaged for each chromosome to reduce noise. Green to red ratios greater than 1.20 were considered as gains of genetic material, and ratios less than 0.80 were considered as losses. Heterochromatic regions in the centromeric and paracentromeric parts of some chromosomes and the short arm of the acrocentric chromosomes were not included in the evaluation.

Mutation analysis of the MEN1 gene

Mutation analysis was performed using single strand conformation analysis and direct sequencing. The 9 coding exons of the MEN1 gene were amplified using 15 different fragments of 200–300 bp each, as previously described (4). When a single strand conformation-shifted band was detected, the original DNA sample was sequenced on a 377 automated fluorescent sequencer (Applied Biosystems).

Loss of heterozygosity analysis

Constitutional and tumor DNA from five of the irradiation-associated tumors were genotyped for the microsatellite markers D11S449 and PYGM located close to and flanking the MEN1 gene on chromosome 11q13. PCR were performed according to standard procedures, and the PCR products were electrophoresed in polyacrylamide gel followed by autoradiography. The results are detailed in Table 2.

Statistical analysis

Correlation between CGH aberrations and clinical features was analyzed using the Mann-Whitney U test in the StatView 4.0 software (SAS Institute, Inc., Cary, NC). P < 0.05 was accepted as significant.

	Results

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CGH alterations in sporadic, irradiation-associated, and familial parathyroid tumors

The gains and losses found are detailed for each tumor in Tables 1–3 together with the clinical information. The subchromosomal regions with increased and decreased DNA sequence copy number are illustrated in Fig. 1. In general, losses were twice as common as gains. No statistically significant correlation was found between any of the copy number changes and the clinical parameters, i.e. serum calcium, serum PTH, and tumor weight. However, a tendency to an association between gain of 19p and high serum calcium levels was noted (P = 0.056).

View larger version (31K): [in this window] [in a new window]   Figure 1. Summary of DNA copy number alterations detected by CGH in the 26 sporadic, 10 irradiation-associated, and 8 familial parathyroid tumors analyzed. Each line represents one alteration detected in one tumor, with losses illustrated to the left and gains to the right of the ideograms.

View larger version (10K): [in this window] [in a new window]   Figure 2. The data points in the diagram at the top illustrate the number of CGH alterations detected in each of the 44 parathyroid tumors. At the bottom are given the median and mean numbers of aberrations and total number of tumors (n) in the different clinico-pathological subgroups.

The tumors from patients previously given irradiation to the neck showed multiple aberrations, in 6 of the 10 cases involving 4–10 regions (Table 2). The mean number of alterations per tumor was 4.3 (Fig. 2), which is significantly more than that detected in adenomas not associated with irradiation (P < 0.01). The changes in this tumor type preferentially involved losses of 1p (50%), 11q13-qter (50%), 11p12-p14 (40%), 6q16-q26 (30%), 18q (30%), and 22q (30%), but gains of 19p13.2-pter were also seen repeatedly (30%). In 1 case (no. RA-4 and 5) we had access to tumor material from 2 different operations. This is a 54-yr-old man who at 6 yr of age was subject to head and neck irradiation for tonsillitis. He later developed a papillary thyroid cancer, which was operated on at age 29 yr. Since 1984 he has had 5 operations for recurrent hyperparathyroidism, and here we have analyzed material from the fourth and fifth procedures. The CGH analysis showed loss of 1p and 11p in both cases and, additionally, gain of 19p in the tumor from last exploration (Table 2).

MEN1 mutations in irradiation-associated parathyroid tumors

The genetic profile obtained for the irradiation-associated adenomas closely resembles that of the ordinary adenomas with involvement of the MEN1 gene, i.e. multiple CGH alterations and frequent losses of 11q. Mutation analysis of MEN1 was therefore performed in the eight cases for which tumor DNA was still available. Mutations were detected in four tumors (50%), three of which showed 11q loss by CGH. The mutations included one small deletion in exon 8 resulting in a frame shift, one insertion of an amino acid in exon 7, and two missense mutations in exons 3 and 10 causing incorporation of a different amino acid (Table 2). In the two cases where we had access to corresponding normal DNA (RA-7 and RA-10), the normal nucleotide sequence was found in the constitutional DNA, thus confirming the mutations as somatic.

	Discussion

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The present analysis demonstrate that the majority of parathyroid tumors harbor DNA sequence copy number alterations involving one or more chromosomal regions. In eight of the sporadic adenomas no CGH alterations were detected, which could be due to balanced aberrations not affecting DNA sequence copy number or aberrations beyond the resolution capacity of CGH. To get a better resolution of losses within a small chromosomal region, LOH studies using microsatellite markers are performed. In this study the overall concordance between CGH and LOH results for the 11q13 region was good. All cases of 11q13 loss detected by CGH were also detected by LOH. However, four adenomas demonstrated LOH at MEN1 in 11q13, but did not display any loss of chromosome 11 by CGH, although the two analysis were performed on the same DNA preparations.

In other types of tumors the grade of malignancy is correlated to the observed genomic instability, with few alterations in benign tumors and multiple alterations in highly malignant cases (14). However, in this study DNA copy number changes occurred frequently in the adenomas, with 1–10 alterations detected in 83% of the cases. Similar results have been obtained in 2 other studies of parathyroid adenomas (12, 15).

Overall losses were most frequently detected on chromosome 11, followed by chromosomes 15q and 1p. With regard to the clinico-pathological subtypes analyzed, loss of 11 was only demonstrated in the sporadic adenomas with MEN1 involvement and in the irradiation-associated tumors, whereas loss of 1p occurred in all subtypes of nonfamilial tumor, and loss of 15q was found in both familial and nonfamilial cases. These three regions have also been identified as frequently lost in LOH analysis of sporadic parathyroid adenomas (10). In LOH studies the 11q13 and 1p regions have been studied in some detail and are found to be lost in up to a third of the cases (16, 17) (Dwight, T., et al., unpublished observations). In approximately half of the parathyroid tumors with 11q13 LOH, a concomitant MEN1 mutation has been reported, whereas no mutations have been demonstrated in tumors without 11q13 LOH. RA-7 in this study provides the first exception to this rule. The lack of 11q13 LOH together with the presence of a MEN1 mutation in this case could be explained by intragenic deletions or mutations not detectable with the method applied.

Gain of 19p13.2-pter occurred frequently in this material (23%) and was detected in all subtypes of parathyroid tumors. This region of chromosome 19 harbors a second locus for FHH (18). In addition, a third locus has recently been mapped to 19q (19). The first FHH gene identified was the calcium receptor CaR in 3q (20). Constitutional mutations of CaR can give rise to a whole spectra of phenotypes affecting calcium homeostasis and in homozygous form giving rise to parathyroid adenomas. Interestingly, gain of 19p was detected as the only abnormality in three of the six adenomas from familial cases that could not be associated with the MEN1 or HRPT2 loci.

The MEN1 tumor suppressor gene was recently cloned, but as it has no homology to previously known genes its function has remained unknown. Here we have subdivided sporadic adenomas from previously characterized material into two groups based on the involvement of the MEN1 gene locus. A higher frequency of CGH alterations was seen in the sporadic adenomas with MEN1 mutation and/or LOH than in sporadic adenomas without MEN1 involvement. Although the difference is not statistically significant, the result is in agreement with observations of chromosomal instability and premature centromere division in lymphocytes from MEN 1 patients (21, 22).

Available genetic data on irradiation-associated parathyroid adenomas have been limited (11). The cases analyzed in this series displayed multiple alterations, most commonly involving loss of 11q and 1p, which were seen in five cases each. This genetic profile closely resembles that of the ordinary adenomas with involvement of the MEN1 gene, suggesting a common genetic background. Indeed, inactivating mutations of the MEN1 gene were identified in four of the eight tumors analyzed. The mutations detected are likely to delete or alter the function of the menin protein. One frame shift was detected that most likely gives rise to a truncated protein, resulting in loss of function of the gene. Furthermore, by comparison with the murine MEN1 sequence (23), the two missense mutations were shown to affect conserved amino acids. The findings suggest that the MEN1 gene can be mutated/inactivated using irradiation. An alternative explanation would be that genomic instability induced by irradiation causes the mutation of the MEN1 gene. In either case, inactivation of the MEN1 gene seems to be an important genetic alteration contributing to the development of parathyroid tumors in these patients.

	Acknowledgments

 
The authors thank Ritva Karhu and Marketta Kähkönen, Laboratory of Cancer Genetics, University of Tampere (Tampere, Finland), for valuable technical advise.

	Footnotes

 
¹ This work was supported by the Swedish Cancer Society, the Torsten and Ragnar Söderberg Memory Foundations, the Gustav V Jubilee Fund, the Swedish Society for Medical Research, the Swedish Medical Research Council, the Cancer Society of Stockholm, and the Fredrik and Ingrid Thuring Foundation.

² Supported by the Wenner-Gren Foundation.

Received December 7, 1998.

Revised February 17, 1999.

Revised June 15, 1999.

Accepted July 15, 1999.

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