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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1766-1770
Copyright © 1998 by The Endocrine Society

Original Studies

Novel Chromosomal Abnormalities Identified by Comparative Genomic Hybridization in Parathyroid Adenomas1

Nallasivam Palanisamy, Yasuo Imanishi, Pulivarthi H. Rao, Hideki Tahara, R. S. K. Chaganti and Andrew Arnold

Cell Biology Program (N.P., P.H.R., R.S.K.C.), Memorial Sloan-Kettering Cancer Center, New York, New York 10021; Laboratory of Endocrine Oncology (Y.I., H.T., A.A.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; and Center for Molecular Medicine (Y.I., A.A.), University of Connecticut School of Medicine, Farmington, Connecticut 06030-1316

Address all correspondence and requests for reprints to: Dr. Andrew Arnold, Center for Molecular Medicine and Division of Endocrinology and Metabolism, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, Connecticut 06030-1316.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The molecular basis of parathyroid adenomatosis includes defects in the cyclin D1/PRAD1 and MEN1 genes but is, in large part, unknown. To identify new locations of parathyroid oncogenes or tumor suppressor genes, and to further establish the importance of DNA losses described by molecular allelotyping, we performed comparative genomic hybridization (CGH) on a panel of 53 typical sporadic (nonfamilial) parathyroid adenomas. CGH is a new molecular cytogenetic technique in which the entire tumor genome is screened for chromosomal gains and/or losses. Two abnormalities, not previously described, were found recurrently: gain of chromosome 16p (6 of 53 tumors, or 11%) and gain of chromosome 19p (5 of 53, or 9%). Losses were found frequently on 11p (14 of 53, or 26%), as well as 11q (18 of 53, or 34%). Recurrent losses were also seen on chromosomes 1p, 1q, 6q, 9p, 9q, 13q, and 15q, with frequencies ranging from 8–19%. Twenty-four of the 53 adenomas were also extensively analyzed with polymorphic microsatellite markers for allelic losses, either in this study (11 cases) or previously (13 cases). Molecular allelotyping results were highly concordant with CGH results in these tumors (concordance level of 97.5% for all informative markers/chromosome arms examined).

In conclusion, CGH has identified the first two known chromosomal gain defects in parathyroid adenomas, suggesting the existence of direct-acting parathyroid oncogenes on chromosomes 16 and 19. CGH has confirmed the locations of putative parathyroid tumor suppressor genes, also defined by molecular allelotyping, on chromosomes 1p, 6q, 9p, 11q, 13q, and 15q. Finally, CGH has provided new evidence favoring the possibility that distinct parathyroid tumor suppressors exist on 1p and 1q, and has raised the possibility of a parathyroid tumor suppressor gene on 11p, distinct from the MEN1 gene on 11q. CGH can identify recurrent genetic abnormalities in hyperparathyroidism, especially chromosomal gains, that other methods do not detect.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PARATHYROID adenomas are benign clonal tumors that are the most common cause of primary hyperparathyroidism. Two specific genes have been solidly identified as participating in their pathogenesis: the cyclin D1/PRAD1 oncogene (1, 2, 3) and the MEN1 tumor suppressor gene on 11q13 (4, 5), each being overexpressed or homozygously inactivated, respectively, in about 20% of sporadic nonfamilial parathyroid adenomas. In addition, molecular allelotyping studies, using microsatellite markers, have revealed recurrent losses of DNA from chromosomes 1, 6, 9, and 15 in parathyroid adenomas (6, 7, 8), highlighting the likelihood that still-unidentified tumor suppressor genes, whose acquired inactivation contributes to parathyroid neoplasia, may reside in these genomic locations. Losses on 13q that include the RB gene have been observed more frequently in aggressive parathyroid tumors or parathyroid malignancies than in benign adenomas (7, 9, 10, 11).

Given the heterogeneous molecular defects found in most types of human neoplasms, and the general expectation that multiple oncogenic lesions are needed for the outgrowth of any single tumor, we sought to identify new locations of parathyroid adenoma oncogenes or tumor suppressor genes. We applied a new molecular cytogenetic technique called comparative genomic hybridization (CGH), in which an entire tumor genome is screened simultaneously for chromosomal gains and/or losses (12). The CGH approach has been successfully applied in a number of solid human tumors (13, 14, 15, 16) and is nicely complementary to molecular allelotyping, a method of high local resolution but low adequacy for detecting chromosomal gains and whose comprehensiveness is limited by the number of specific marker loci examined.

Fifty-three typical sporadic (nonfamilial) parathyroid adenomas were analyzed by CGH. In addition, many of these same adenomas were subjected to an extensive molecular search for allelic losses using traditional microsatellite markers, permitting a comparison and joint interpretation of results obtained with both complementary methods.


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

Parathyroid adenoma tissue samples were obtained from unselected patients undergoing parathyroidectomy for management of primary hyperparathyroidism. All were surgically and pathologically proven to have parathyroid adenomas, i.e. single gland disease. No sample had any feature suggesting malignancy. No patients had a known history of head or neck irradiation, nor a clinical/family history suggestive of a multiple endocrine neoplasia or familial hyperparathyroidism syndrome. After surgical removal, tumor tissue was carefully dissected, frozen in liquid nitrogen and stored at -80 C before extraction of genomic DNA by standard methods (17). DNA from patients’ paired venous blood samples was also extracted and used in microsatellite analyses. Both tumor and blood samples were obtained in accordance with Institutional Review Board oversight.

CGH

Fifty-three parathyroid adenoma genomic DNA samples were analyzed by CGH. CGH was performed essentially as described (18). Briefly, the probe tumor DNA and normal reference DNA were labeled differentially by standard nick translation using fluorescein 12-deoxyuridine 5-triphosphate and Texas Red 5-deoxyuridine 5-triphosphate (NEN-Dupont, Boston, MA), respectively. Equal amounts (500 ng) of tumor and normal reference DNA were coprecipitated with 25 µg unlabeled human Cot-1 DNA (Gibco-BRL, Gaithersburg, MD). The Cot-1 DNA is included to suppress the binding of the labeled DNA from both genomes to the centromeric and heterochromatic regions of the normal chromosomes. The probe DNA was resuspended in 15 µL hybridization mixture (50% formamide, 2x saline-sodium citrate (SSC), 10% dextran sulphate) and hybridized to normal human metaphase chromosomes prepared by phytohemagglutinin-stimulated peripheral blood lymphocyte culture. The hybridization was performed at 37 C for 48 h. The slides were washed at 45 C, three times, for 5 min each in 50% formamide/2x SSC, followed by three washes (5 min each) at 45 C in 2x SSC and once in 0.1x SSC for 10 min. The chromosomes were counterstained with 4,6-diamino-2-phenylindole for the identification of the chromosomes.

Digital image analysis. The green and red fluorescence intensities of the hybridization signals, and 4,6-diamino-2-phenylindole staining patterns, were captured with a cooled charge-coupled device camera (Photometrics, Tucson, AZ) attached to a Nikon Microphot-SA microscope. Fluorescence ratio profiles for each chromosome were calculated using the Quantitative Image Processing System (QUIPS, Vysis Inc., Downers Grove, IL). For each hybridization, the data from 12–14 representations of each chromosome were combined to obtain the mean and 95% confidence interval for that ratio, plotted next to the ideogram for that chromosome. Gains or losses of chromosomes or chromosomal regions were detected on the basis of the ratio profiles deviating from the green to red balance value of 1.0. The upper and lower threshold limits for defining chromosomal gains and losses were set to 1.20 and 0.80, respectively. These threshold values were determined by CGH experiments using two differentially labeled normal genomic DNA samples. In these negative control experiments, the mean green to red ratio was well within 1.20–0.80 over the entire length of all chromosomes, thus providing robust and highly stringent criteria for the determination of gains and losses in tumor samples. Metaphase spreads, with uniform high intensity fluorescence in both green and red colors on both homologous chromosomes and with no background spots, were selected for evaluation. The centromeric and heterochromatic regions and p arm of acrocentric chromosomes and telomeric regions were not included in the interpretation of gains and losses.

Allelic loss analyses using microsatellite polymorphisms

Eleven of the 53 parathyroid adenomas examined with CGH were also extensively analyzed with polymorphic microsatellite markers for allelic losses. An additional 13 of these 53 cases had previously been allelotyped with molecular markers (7), yielding a total of 24 adenomas subjected to both CGH and molecular allelotyping. Figure 3Go contains our group’s accumulated molecular allelotyping results for a total of 55 parathyroid adenomas, which include 25 previously reported (7) and 30 recently analyzed cases. Primers for PCR amplification of microsatellite markers, chosen to represent every chromosome arm except the short arm of acrocentric chromosomes, were obtained from Research Genetics (Huntsville, AL) or synthesized on a DNA synthesizer (Applied Biosystems, Foster City, CA). The 42 primer pairs and genomic loci analyzed here were identical to those examined in our previous study (7), with the following additions: D6S264 (6q), D15S165 (15q), and DXS1237 (Xp), and the following substitutions: D13S153 instead of D13S168 (13q), and DCC instead of D18S46 (18q). Primer labeling, PCR amplification of paired tumor and leukocyte genomic DNA, analysis of PCR products, and scoring of allelic losses were as previously described (7).



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  		Figure 3. Frequency of allelic loss, by molecular allelotyping methodology, on each chromosomal arm in 55 parathyroid adenomas. LOH (%) represents the percentage of tumors showing allelic loss on each chromosome arm. Allelotyping was performed as described in Materials and Methods. These data are a comprehensive summary of allelotyping results obtained previously (7) on 25 tumors, plus new results from an additional 30 adenomas. Among these 55 adenomas are 24 that were also in the group of 53 examined by CGH in the present study.

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Fifty-three parathyroid adenoma DNA samples were analyzed by CGH. Thirty-eight tumors (72%) showed clonal chromosomal imbalances that include gains and losses of whole, or part of the, chromosomes. Among the 38 tumors, 31 had 2 or more chromosomal changes. Chromosomal losses were more commonly observed than were chromosomal gains (91 vs. 27). Two abnormalities, not previously described in parathyroid adenomas, were found recurrently: gain of chromosome 16p (6 of 53 tumors, or 11%) and gain of chromosome 19p (5 of 53, or 9%). 19q was also included in the area of gain in 4 of these tumors (8%). The most frequent abnormality detectable by CGH in the adenomas was loss of chromosome 11q (18 of 53 tumors, or 34%). The extent of loss in many of these tumors also included 11p (14 of 53, or 26%); and interestingly, 11p loss in one tumor (no. 974) was not accompanied by 11q loss. Loss of chromosomal regions was recurrently detected in chromosomes 1p (10 of 53, or 19%), 1q (6 of 53, or 11%) with a consensus region at 1q42–44, and mostly noncontiguous with (or in separate tumors than those with) 1p losses, 6q (6 of 53, or 11%), 9p (4 of 53, or 8%), 9q (5 of 53, or 9%), 13q (10 of 53, or 19%) and 15q (9 of 53, or 17%). Regions of genetic gain or loss that were found in less than 8% of the parathyroid adenomas included: losses of 2p23–25, 12p12–13, 18q, 22, and X, and gain of 1q with a consensus region at 1q31 and 5q with a consensus region at 5q34–35, each in 3 of 53 tumors (6%); losses of 2q36–37, 4, and gain at 1p36, each in 2 of 53 tumors (4%). Losses at 3q13.2–13.3, 5p, 7p21–22, 10q23, 14q, 17p, 19, 20, and 21, and gain of 1p12–32, 2p23–25, 3q25–29, 6, 7p14–22, 8, 14q, and 17pter-q21 were each found in 1 of 53 tumors (2%). A comprehensive summary of the CGH analyses for all the tumors is presented in Fig. 1Go. Representative CGH images with fluorescence ratio profiles and corresponding ideograms for recurrent chromosomal gains and losses are shown in Fig. 2Go.



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  		Figure 1. DNA copy number changes in 53 parathyroid adenomas. Summary of all gains and losses detected by CGH. The vertical bars on the left side of the chromosome ideograms indicate losses and those on the right side indicate gains of the corresponding chromosomal region for each individual tumor, as numbered.

 


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  		Figure 2. Representative CGH results in parathyroid adenomas. Individual examples of fluorescent ratio profiles (right) and digital images (left) of chromosomes with recurrent gains or losses. The red vertical bar on the left side of a chromosome ideogram (middle) indicates the region of loss and the green vertical bar on the right side of an ideogram indicates the region of gain.

 
Of the 53 parathyroid adenomas that were examined by CGH, 24 were also extensively analyzed with polymorphic microsatellite markers for allelic losses, either in this study (11 cases) or previously (13 cases) (7). Molecular allelotyping results were remarkably concordant with CGH results in these tumors. Cumulatively, for all 761 informative markers examined over all 24 tumors, allelic loss was found with 29 markers (3.8%) for which the corresponding chromosome region was also lost by CGH. For 713 total markers (93.7%), allelic loss was not observed; and the corresponding chromosomal region showed no loss by CGH. Molecular analysis showed allelic loss in only 9 instances (1.2%) for which the corresponding region showed no loss by CGH. Only 10 times (1.3%) did the analyzed molecular markers fail to show allelic loss when loss of the corresponding chromosome region was seen by CGH. Thus, the overall concordance level between molecular allelotyping and CGH was 97.5% for all informative markers/chromosome arms examined, and the discordancy rate was only 2.5%. Figure 3Go summarizes our cumulative molecular allelotype data on a total of 55 parathyroid adenomas, which include this subset of 24 adenomas also analyzed by CGH in the present study.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We performed CGH on a panel of 53 typical sporadic (nonfamilial) parathyroid adenomas to identify new locations of parathyroid oncogenes or tumor suppressor genes, and to further establish the importance of DNA losses previously described by molecular allelotyping. Our results indicate that CGH is an important new addition to the armamentarium of investigators of endocrine tumorigenesis. Unlike molecular allelotyping with microsatellite markers or restriction fragment length polymorphisms, widely used to identify specific genomic sites of allelic loss or loss of heterozygosity (LOH), CGH is capable of definitively revealing regions of the tumor genome present in extra copy number. Recurrently identified regions of chromosomal gain presumably conferred a selective growth advantage upon the tumor cell, and they likely harbor one or more direct-acting oncogenes whose overexpression contributes to tumorigenesis. CGH has identified the first 2 known chromosomal gain defects in parathyroid adenomas, suggesting the existence of direct-acting parathyroid oncogenes on chromosomes 16 and 19. Study of more tumors may help narrow the still-large target regions in search of the pathogenic oncogenes, and analysis of candidate oncogenes mapping to these chromosomal locations may also prove fruitful.

In the detection of regions of chromosomal loss in the tumor genome, CGH yields information different from and complementary to that obtained from allelotyping. CGH offers a comprehensive scanning of the entire tumor genome, but at modest resolution; it is estimated that a region of loss would need to encompass 20–30 megabases to be detected (19). Allelotyping detects loss at the highly specific molecular marker locus analyzed; very small losses are potentially detectable, but only if the markers happen to fall within the region of loss. Furthermore, microsatellite analyses actually detect allelic imbalance, and an amplification of one allele could be mistakenly interpreted as loss of the other allele. It is, therefore, intriguing that our CGH study identified the same regions of chromosomal loss that had been discovered as areas of LOH with a marker density of 1–2 per chromosome arm, and that no additional areas of frequent loss were identified by CGH. These observations confirm that acquired genetic losses on chromosomes 1, 6, 9, 11, 13, and 15 in parathyroid adenomas are, in fact, true losses of tumor DNA, suggest that these losses tend to be large in scale, and provide a clue that most areas of major chromosomal loss in parathyroid adenomas may now have been discovered.

At least one target of the frequent losses found on chromosome 11 in parathyroid adenomas is the MEN1 tumor suppressor gene on 11q13. Heppner et al. (5) found somatic MEN1 gene mutations, plus loss of the other allele, in 4 of 24 parathyroid adenomas (17%). However, allelic losses on 11q have been observed in up to 39% of adenomas (5, 7) and were seen in 34% of our tumors by CGH. Thus, our CGH data reinforce the possibility that a critical parathyroid tumor suppressor gene may lie on chromosome 11, distinct from the MEN1 gene on 11q13. Because loss of 11p was typically found in contiguity with 11q loss by CGH in our cases, and especially because one tumor revealed loss of 11p with no loss of 11q, it is possible that one such additional putative tumor suppressor is located on 11p.

The frequency of chromosome 13q loss by CGH was 19% and was 13% by molecular allelotyping (Fig. 3Go), as compared with 5–11% frequencies previously described in typical benign adenomas (7, 9). Whereas loss of 13q does seem to occur at much higher frequencies in aggressive parathyroid tumors including parathyroid carcinomas (9, 10, 11), our results emphasize that the diagnostic use of molecular genetic analyses to distinguish benign from potentially aggressive parathyroid tumors will likely require analysis of a panel of such markers or chromosomal regions, rather than any single one, to attain statistical and clinical significance. CGH may eventually be used, therefore, to provide clinically relevant information in the often-difficult categorization of parathyroid adenomas with atypical or aggressive features.

Among parathyroid adenomas, the frequent occurrence of specific clonal chromosomal alterations strongly attests to their pathogenetic importance and argues against their being the functionally irrelevant result of increased genomic instability in the tumor cell. Furthermore, the observed heterogeneity of acquired genetic abnormalities within and among individual parathyroid adenomas is consonant with the heterogeneity generally found in human neoplasms. Thus, in benign endocrine tumors, as well as cancers, multiple hits are likely to be necessary for a cell to acquire a clinically significant selective advantage over its normal neighbors. Finally, our observations emphasize that the different genetic abnormalities observed among individual parathyroid adenomas can result in a very similar and typical, clinical and biochemical phenotype.


   Footnotes
 
1 This work was supported, in part, by NIH Grant DK-11794 and a Faculty Research Award from the American Cancer Society (to A.A.). Back

Received October 7, 1997.

Revised January 21, 1998.

Accepted January 29, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Motokura T, Bloom T, Kim HG, et al. 1991 A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 350:512–515.[CrossRef][Medline]
  2. Arnold A. 1995 The cyclin D1/PRAD1 oncogene in human neoplasia. J Investig Med. 43:543–549.[Medline]
  3. Hsi ED, Zukerberg LR, Yang WI, Arnold A. 1996 Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study. J Clin Endocrinol Metab. 81:1736–1739.[Abstract]
  4. Chandrasekharappa SC, Guru SC, Manickam P, et al. 1997 Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 276:404–407.[Abstract/Free Full Text]
  5. Heppner C, Kester MB, Agarwal SK, et al. 1997 Somatic mutation of the MEN1 gene in parathyroid tumours. Nat Genet. 16:375–378.[CrossRef][Medline]
  6. Cryns VL, Yi SM, Tahara H, Gaz RD, Arnold A. 1995 Frequent loss of chromosome arm 1p DNA in parathyroid adenomas. Genes Chromosom Cancer. 13:9–17.[Medline]
  7. Tahara H, Smith AP, Gaz RD, Cryns VL, Arnold A. 1996 Genomic localization of novel candidate tumor suppressor gene loci in human parathyroid adenomas. Cancer Res. 56:599–605.[Abstract/Free Full Text]
  8. Tahara H, Smith AP, Gaz RD, Arnold A. 1996 Loss of chromosome arm 9p DNA and analysis of the p16 and p15 cyclin-dependent kinase inhibitor genes in human parathyroid adenomas. J Clin Endocrinol Metab. 81:3663–3667.[Abstract]
  9. Cryns VL, Thor A, Xu H-J, et al. 1994 Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N Engl J Med. 330:757–761.[Abstract/Free Full Text]
  10. Dotzenrath C, Teh BT, Farnebo F, et al. 1996 Allelic loss of the retinoblastoma tumor suppressor gene: a marker for aggressive parathyroid tumors? J Clin Endocrinol Metab. 81:3194–3196.[Abstract]
  11. Pearce SH, Trump D, Wooding C, Sheppard MN, Clayton RN, Thakker RV. 1996 Loss of heterozygosity studies at the retinoblastoma and breast cancer susceptibility (BRCA2) loci in pituitary, parathyroid, pancreatic, and carcinoid tumours. Clin Endocrinol (Oxf). 45:195–200.[CrossRef][Medline]
  12. Kallioniemi A, Kallioniemi OP, Sudar D, et al. 1992 Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science. 258:818–821.[Abstract/Free Full Text]
  13. Ried T, Knutzen R, Steinback R, et al. 1996 Comparative genomic hybridization reveals a specific pattern of chromosomal gains and losses during the genesis of colorectal tumors. Genes Chromosom Cancer. 15:234–245.[CrossRef][Medline]
  14. Kallioniemi A, Kallioniemi OP, Citro G, et al. 1995 Identification of gains and losses of DNA sequences in primary bladder cancer by comparative genomic hybridization. Genes Chromosom Cancer. 12:213–219.[Medline]
  15. Korn WM, Daniel EM, Weghuis O, et al. 1996 Detection of chromosomal DNA gains and losses in testicular germ cell tumors by comparative genomic hybridization. Genes Chromosom Cancer. 17:78–87.[CrossRef][Medline]
  16. Levin NA, Brzoska PM, Warnock ML, Gray JW, Christman MF. 1995 Identification of novel regions of altered DNA copy number in small cell lung tumors. Genes Chromosom Cancer. 13:175–185.[Medline]
  17. Sambrook J, Fritsch EF, Maniatis T. 1989 Molecular cloning. A laboratory manual. 2nd ed. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory; 9.16–9.19.
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Vitamin D Receptor as a Candidate Tumor-Suppressor Gene in Severe Hyperparathyroidism of Uremia
J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 868 - 872.
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F. Farnebo, S. Kytola, B. T. Teh, T. Dwight, F. K. Wong, A. Hoog, M. Elvius, W. S. Wassif, N. W. Thompson, L.-O. Farnebo, et al.
Alternative Genetic Pathways in Parathyroid Tumorigenesis
J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3775 - 3780.
[Abstract] [Full Text] [PDF]

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S. J. Marx
CLINICAL REVIEW 109: Contrasting Paradigms for Hereditary Hyperfunction of Endocrine Cells
J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3001 - 3009.
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