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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 525-530
Copyright © 1998 by The Endocrine Society

Original Studies

Studies of Allelic Loss in Thyroid Tumors Reveal Major Differences in Chromosomal Instability between Papillary and Follicular Carcinomas1

Laura S. Ward, Gabriela Brenta, Mario Medvedovic and James A. Fagin2

Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0547

Address all correspondence and requests for reprints to: James A. Fagin, M.D., Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, P.O. Box 670547, Cincinnati, Ohio 45267-0547. E-mail: faginja{at}uc.edu


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Discussion
 References
 
Loss of heterozygosity (LOH) studies have been used to identify sites harboring tumor suppressor genes involved in tumor initiation or progression. Previous reports have suggested that regions within chromosomes 3p, 11q, 2p, 2q, 10q, and 1p may be frequently deleted in human follicular thyroid cell tumors. We have extended the analysis of these and other selected regions to 65 paired thyroid tumor tissues. Twenty-four were follicular adenomas, 30 were papillary carcinomas, 10 were follicular carcinomas, and 1 was an anaplastic carcinoma. Sixty percent of the follicular carcinomas, 33% of the follicular adenomas, and 23% of the papillary carcinomas presented LOH at least at 1 site. Fifty percent of the follicular carcinomas showed 2 or more chromosome arms affected by deletions, whereas just 1 of the 24 follicular adenomas and none of the papillary carcinomas presented this feature. However, none of the specific loci examined had a rate of LOH greater than 33%, even in follicular carcinomas. This prompted us to place our findings into a broader context, and we, therefore, performed a meta analysis of all published studies of LOH in follicular thyroid neoplasms. There was a phenotype dependency in the overall rate of LOH, with no specific region displaying a particularly high prevalence. Most notably, by contrast to follicular carcinomas, papillary carcinomas had exceedingly low rates of LOH. Thus, there is a sharp distinction between the two major forms of differentiated thyroid cancer in their tendency to lose genetic material. This probably results from a fundamental difference in mechanisms controlling chromosomal stability in these two forms of cancers that in all likelihood has implications for tumor behavior and prognosis.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Discussion
 References
 
THYROID cancers, like other human tumors, arise from a single transformed cell that presumably gained growth advantage through damage to genes that control cellular proliferation (1, 2). The neoplastic clone, in which proliferative controls are disrupted, may also have a higher propensity to develop further genetic abnormalities (3). As the genome becomes unstable, the cell is more prone to develop large scale chromosome aberrations, amplifications, deletions, and translocations. The consequent accumulation of genetic abnormalities is associated with increasing genetic heterogeneity in the tumor clone and with a more aggressive and invasive behavior (4, 5). A frequently measured manifestation of chromosomal instability is allelic deletions, primarily detected through highly polymorphic markers for which tumors lose one of the heterozygous bands. Several groups have performed loss of heterozygosity (LOH) studies in benign and malignant thyroid tumors (6, 7, 8, 9, 10, 11, 12, 13, 14). Certain chromosomal regions, such as 3p, 2p, 2q, 10q, and 11q, have been reported to be more frequently subject to allelic loss and have, therefore, been proposed to harbor important tumor suppressors for thyroid cancer. In this study, we targeted those regions and several others for further examination. In addition, we undertook a meta analysis of all published reports of LOH in thyroid tumors. In our study as well as in the cumulative data from the literature, there appears to be no major increase in the rate of LOH on chromosome 3p, 2p, or any specific locus compared to that in other regions. However, the overall prevalence of allelic deletions was much higher in follicular carcinomas than in follicular adenomas. Remarkably, papillary thyroid carcinomas have an exceedingly low prevalence of LOH at all sites examined by multiple investigators. The sharp contrast in prevalence of allelic deletions between papillary and follicular carcinomas suggests that there is a fundamental difference in factors controlling chromosomal integrity in the two main types of differentiated thyroid carcinomas that may ultimately impact on their clinical behavior and response to therapy.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Discussion
 References
 
Tissues specimens

We studied 65 thyroid tumors, all them paired with their corresponding normal tissue obtained from adjacent parts of the gland. Tissues from 60 patients were snap-frozen in liquid N2, and 5 specimens were from paraffin blocks. Twenty-four tumors were follicular adenomas (16 well differentiated, 8 atypical), 30 were papillary carcinomas, 10 were follicular carcinomas, and 1 was anaplastic carcinoma. Three of the follicular carcinomas displayed minimal invasiveness, whereas 7 were widely invasive. Twenty of the 30 papillary carcinomas had no evidence of distant metastasis at the time of surgery. None of these patients had a history of radiation exposure.

DNA isolation

Both normal and tumoral tissues were carefully microdissected from the cryostat or the paraffin blocks. The frozen tissues were ground under liquid N2, and the DNA was extracted using a cesium chloride ultracentrifugation gradient (15). Five to 10 slides of 15 µm were cut from each of the paraffin-embedded tissue blocks and digested with proteinase K for 16 h. After phenol/chloroform extraction, the samples were ethanol precipitated and then resuspended. The DNA concentration was determined by 260/280 spectrophotometry. Samples were stored at -20 C until assayed.

LOH analysis

Thirty-eight pairs of primers (Research Genetics), representing 16 chromosome arms, were used to amplify polymorphic microsatellite repeats (Table 1Go).


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  		Table 1. Locations of the chromosome markers used in this study

 
The markers were selected based on regions where higher rates of LOH had been described previously (6, 7, 8, 9, 10, 11, 12, 13, 14). We also targeted well characterized loci such as that harboring the multiple endocrine neoplasm type 1 gene (11q13), and the TSG101 gene (11p15.1–15.2) (16). Chromosome 16 was explored based on our studies using comparative genomic hybridization that identified this region as frequently deleted in thyroid tumors (17). One primer of each pair was labeled with polynucleotide kinase and [{gamma}-32P]ATP. PCR mixtures were prepared with 100 nmol/L of each primer and 200 µmol/L of each dinucleotide triphosphate. MgCl2 concentrations ranged from 0.7–2.5 mmol/L. Annealing temperatures varied with each primer from 55–62 C, and amplifications were carried out for 35 cycles. PCR products were mixed with a denaturing dye and heated for 3 min at 95 C. After this, they were resolved by electrophoresis on 8% acrylamide gels for 3–6 h at 45–50 C. Allelic fragments were visualized by autoradiography. After that, the same gels were exposed to a PhosphoImager (Molecular Dynamics, Sunnyvale, CA) for quantitative scanning, and the ratio of allele intensities in the tumor relative to that in corresponding normal control tissue was calculated using the following formula (18): imbalance factor = [(Na/Nb)/(Ta/Tb)], where Na is the intensity of allele a in the normal tissue DNA, Nb is the intensity of allele b in the normal tissue DNA, Ta is the intensity of allele a in the tumor DNA, and Tb is the intensity of allele b in the tumor DNA.

For informative, i.e. heterozygous cases, allelic loss was scored when the intensity of the signal for a tumor allele was significantly reduced relative to that for the matched normal allele. Tumors that had an average imbalance factor greater than 1.7 were classified as presenting LOH at that locus.

Meta analysis of LOH studies in thyroid neoplasms

To combine the relatively small patient populations described in most of the previous LOH studies, we performed a meta analysis of the published papers and abstracts focusing on allelotyping of human thyroid neoplasms (6, 7, 8, 9, 10, 11, 12, 13, 14). Criteria for inclusion was the use of techniques based on allelic polymorphism. Cases were scored as positive when they displayed LOH for at least one marker for the representative chromosome arm. We excluded data where the number of informative cases could not be ascertained.

Statistical analysis

Statistical examination of the meta analysis data and of our results was performed using the Prism software program (GraphPad, San Diego, CA). The overall difference between paired types of tumors was assessed using a modified version of the method proposed by Adams and Skopek (19). Differences in the frequency of allelic deletions between groups at individual sites were assessed using Fisher’s exact test. Individual P values were adjusted for the number of sites compared using Sidak’s procedure (20). The odds ratio (OR) and 95% confidence intervals (CI) provide a measure of the strength of association, e.g. indicating the increase in odds of a given tumor type demonstrating LOH at a particular locus compared to those for tumors of a different phenotype. We assessed the association of LOH in both p and q arms of each chromosome using Pearson’s correlation coefficient.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Discussion
 References
 
The rate of LOH at each chromosome arm is shown in Table 2Go. The percentage of loci that were informative varied from 30–100% of the cases analyzed, with an average of 76%. Representative results of our gels are illustrated in Fig. 1Go, where cases of LOH in many follicular carcinomas and some follicular adenomas are depicted. In contrast, a sequence of 10 informative cases of papillary carcinomas shows the typical pattern found in this tumor type, where LOH is encountered infrequently. Eight of 24 follicular adenomas (33%), 6 of 10 follicular carcinomas (60%), and 7 of 30 papillary carcinomas (23%) had deletions in 1 or more chromosome arms. Follicular carcinomas had a higher average rate of LOH per chromosome arm (25%) than the follicular adenomas (13%) and the papillary carcinomas (9%). Three of the follicular carcinomas presented LOH on multiple sites of the same chromosome [2 cases on chromosome 2 (loci p23-p15, p14-p13, q32, and q33-q37) and one in chromosome 3 (loci p25.3-p25.1, p24.2-p22, and p14.2-p14.1)], indicating that they might have lost a considerable part of the chromosome. Five of the 10 follicular carcinomas had 2 or more chromosome arms affected by LOH. One follicular adenoma showed LOH in all informative sites on chromosome 16q (markers D16S390, D16S411, D16S401, and D16S347), whereas another follicular adenoma had LOH on the centromeric part of both arms of chromosome 3 (loci 3p13-p12 and q11-q13), suggesting a large deletion of the chromosome. There was no significant difference in prevalence of LOH between typical and atypical follicular adenomas. Papillary carcinomas had the lowest average rate of LOH, which was primarily limited to chromosome 10q (15%) and chromosome 11p (11%). Multiple sites of deletion involving different chromosomes were not observed in the papillary carcinomas. There was a statistically significant lower average prevalence of LOH in the papillary carcinomas than in the follicular carcinomas (P < 0.001).


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  		Table 2. Summary of LOH vs. informative cases in each chromosome studied

 


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  		Figure 1. a, Representative examples of allelic deletions in follicular neoplasms. Paired samples of normal thyroid (N) and tumor DNA (T) from each patient are shown. 1 and 2, Samples from follicular carcinoma of same patient, showing LOH at chromosomes 11q13 and 10p11.2. 3 and 4, Paired samples of a follicular carcinoma, showing LOH on 2q32 and 3p24.2-p22, respectively. 5 and 6, Two other follicular carcinomas with LOH on chromosome 11q13 and 2p14-p13, respectively. b, LOH on chromosome 2p24-p21 in third (follicular adenoma) and fifth (follicular carcinoma) sample. c, LOH in a follicular adenoma on chromosome 3p25.3-p25.1. d, Ten cases of papillary carcinoma showing no allelic deletion on chromosome 11q13 (marker D11S2072).

 
Among the follicular carcinomas with LOH, all tumors were widely invasive. By contrast, none of follicular carcinomas with minimal invasion had LOH at the loci tested (P = 0.03). Eighty-six percent (6 of 7) of the papillary carcinomas with evident invasion of the adjacent thyroid tissue and/or extrathyroidal metastasis had LOH, as opposed to only 10% (1 of 10) of the cases restricted to a well defined capsule (P = 0.004). The highest prevalence of LOH for the follicular carcinomas was on chromosomes 11q and 2p (3 of 9) and 3p (3 of 10). The follicular adenomas presented higher rates of LOH on 3p and 10q (2 of 10) and papillary carcinomas on 10q (2 of 13).

The original intent of this study was to focus on those regions identified in prior reports to be more prone to allelic deletions. However, our data did not show any of the studied chromosome loci to be consistently deleted. Because of this, we performed a meta analysis of all published studies of LOH in follicular thyroid neoplasms, where any marker exhibiting LOH was scored as evidence of LOH in the respective chromosome arm (6, 7, 8, 9, 10, 11, 12, 13, 14). Data in Figs. 2Go and 3Go summarize the results of this meta analysis of LOH of a large number of each of the major thyroid tumor phenotypes. The average rate of LOH per chromosome arm was 5.8% for follicular adenomas, 19.7% for follicular carcinomas, and only 2.5% for papillary carcinomas. Papillary carcinomas displayed a remarkably lower rate of LOH than follicular carcinomas (P < 0.001) and follicular adenomas (P < 0.001). In the follicular carcinomas there was a significant association of LOH on both arms of each chromosome, suggesting that there was a high frequency of whole chromosome losses (r = 0.9; P < 0.01).



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  		Figure 2. Summary of the cases of LOH reported in the literature using techniques based on allelic polymorphism. The black portion of the bars represents the number of cases of LOH for each chromosome arm compared with the total number of informative cases reported (gray bar) in Refs. 6–14.

 


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  		Figure 3. Summary of the cases of LOH reported in the literature represented as a percentage of the total number of informative cases per chromosome arm. Data are based on Refs. 6–14.

 

   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
References
 
Loss of function of tumor suppressor genes requires structural or functional inactivation of both alleles. One of these is frequently lost as part of a large deletion of chromosomal material. Therefore, efforts to identify consistent regions of chromosome loss in a given tumor type are a standard way to localize and eventually identify tumor suppressor genes. Higher rates of LOH in thyroid follicular neoplasms have been reported previously on chromosomes 11 (7), 16 (16), 3 (6), 2 (12), 10 (10, 13), and 1 (8). In the present study, we expanded the analysis of these loci and also included a significant number of follicular carcinomas that were not well represented in previous reports from our group and those of others.

We found LOH more frequently in the follicular carcinomas, consistent with some previous publications (9, 10, 11, 12). More than one site of deletion was a common finding among the follicular carcinomas (50% of the cases), suggesting that these tumors, in contrast to the follicular adenomas (4%) and the papillary carcinomas (0%), display a greater degree of genetic instability. This may also account for the relatively high rates of chromosomal abnormalities observed in cytogenetic studies. About 70–80% of follicular and anaplastic carcinomas have chromosomal abnormalities, as determined by standard cytogenetic techniques, in contrast to about 40% of follicular adenomas and papillary carcinomas (21, 22, 23, 24, 25, 26, 27). We also detected a greater overall prevalence of LOH in tumors with a more aggressive or malignant phenotype, in line with data previously reported for the thyroid and other tumors (4, 5, 10). However, we could not identify any single reliable marker able to identify the more aggressive types of thyroid cancer. Chromosome 2 was a frequent site of deletions in follicular carcinomas (33%), consistent with data by Tung et al. (12). In the cumulative data from the literature, chromosome 2p is the site most frequently affected in the follicular carcinomas, but the rate of LOH does not differ from that of follicular adenomas (P = NS). Chromosome 3p is the second most affected chromosome in the literature, an event found more commonly in follicular carcinomas than in adenomas (P = 0.002; odds ratio = 9.0; confidence interval = 2.79–29.41). Although the von Hippel Lindau (VHL) gene is a legitimate candidate in view of its location on consistently deleted regions in 3p (6, 10), more careful mapping revealed that the VHL locus was not a hot spot for LOH in follicular carcinomas (12). Moreover, a recent report could not confirm mutations in exons 1–3 of the VHL gene in thyroid tumors (11). In a previous study, we found chromosome 11q13 deleted in follicular adenomas, but not in papillary carcinomas, suggesting again that this location could harbor a gene involved in the progression toward a follicular phenotype (7). Although other investigators have also found deletions at this locus, the meta analysis does not support a particularly high prevalence of LOH in this region. However, the recent cloning of the multiple endocrine neoplasm type 1 gene will now permit a direct examination of this putative tumor suppressor in thyroid tumorigenesis (28). Thus, LOH appears to be a common feature of follicular neoplasms, particularly follicular carcinomas. Tung et al. have proposed that many of these may actually represent whole chromosome losses arising from chromosome nondisjunction (12). In line with this observation, we found a statistically significant association between loss of the p and q arms of each chromosome in the follicular carcinomas (consistent with whole chromosome loss), but not the papillary carcinomas.

Perhaps the most striking outcome of the meta analysis was the observation that papillary carcinomas have a much lower prevalence of LOH. This is a consistent finding, suggesting that large scale chromosomal instability is not a major feature of these tumors, which correlates well with their favorable prognosis. Thus, we conclude that there is a sharp distinction between the two major forms of differentiated thyroid cancer in their tendency to lose genetic material. This probably results from a fundamental difference in mechanisms controlling chromosomal stability in these two forms of cancer. It is possible that the nature of the tumor-initiating oncogenic event may be significant in determining the genomic stability of the tumor clone (i.e. ras in some follicular neoplasms, ret/PTC in some papillary carcinomas), and that this may have implications for tumor behavior and prognosis.


   Footnotes
 
1 This work was supported in part by NIH Grants CA-50706 and CA-72597. Back

2 Recipient of an Established Investigator Award from the American Heart Association and Bristol Myers-Squibb. Back

Received July 17, 1997.

Revised September 4, 1997.

Accepted October 27, 1997.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 

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Loss of Heterozygosity of the Long Arm of Chromosome 7 in Follicular and Anaplastic Thyroid Cancer, but Not in Papillary Thyroid Cancer
J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3235 - 3240.
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