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Clinical Cancer Research Vol. 9, 1792-1800, May 2003
© 2003 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Classification of Follicular Thyroid Tumors by Molecular Signature

Results of Gene Profiling1

Catherine B. Barden, Katherine W. Shister, Baixin Zhu, Gerardo Guiter, David Y. Greenblatt, Martha A. Zeiger and Thomas J. Fahey, III2

Departments of Surgery [C. B. B., K. W. S., B. Z., D. Y. G., T. J. F.] and Pathology [G. G.], New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York 10021; and Johns Hopkins University School of Medicine, Baltimore, Maryland [M. A. Z.]; and Strang Cancer Prevention Center, New York, New York [T. J. F.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Thyroid nodules are common, with a lifetime risk of developing a clinically significant thyroid nodule of 10% or higher. Preoperative diagnosis was greatly enhanced by the introduction of fine needle aspiration in the 1970s, but there has been little advancement since that time. Discrimination between benign and malignant follicular neoplasms is currently not possible by fine needle aspiration and can even be difficult after full pathologic review. The purpose of these studies is to identify genes expressed in follicular adenomas and carcinomas of the thyroid that will permit molecular differentiation of these neoplasms.

Experimental Design: Gene expression patterns of 17 thyroid follicular tumors were analyzed by oligonucleotide array analysis. Gene profiles for follicular adenomas and carcinomas were identified, and the two groups were compared for differences in expression levels. The differentially expressed genes were used to perform a hierarchical clustering analysis training set. Five follicular tumors with diagnosis undisclosed to the investigators and 2 minimally invasive carcinomas were entered into the cluster analysis as a test set to determine whether diagnosis by gene profile correlated with that obtained by pathologic evaluation.

Results: Thyroid follicular adenomas and carcinomas showed strikingly distinct gene expression patterns. The expression patterns of 105 genes were found to be significantly different between follicular adenoma and carcinoma. Many uncharacterized genes contributed to the distinction between tumor types. For five follicular tumors for which the final diagnosis was undisclosed, the clustering algorithm gave the correct diagnosis in all 5 cases.

Conclusions: Gene profiling is a useful tool to predict the molecular diagnosis of follicular thyroid tumors. Genes were identified that reliably differentiate follicular thyroid carcinoma from adenoma. This study provides insight into genes that may be important in the molecular pathogenesis of follicular thyroid tumors, as well candidates for preoperative diagnosis of follicular thyroid carcinoma.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is estimated that 5–10% of the population will develop a clinically significant thyroid nodule during their lifetime (1) . Although most thyroid nodules are benign, the most common indication for surgical intervention is to exclude the diagnosis of carcinoma. FNA3 was introduced as a preoperative test for thyroid nodules in the 1970’s and validated as a reliable test in numerous studies since that time (2 , 3) . With widespread adoption of thyroid FNA, the likelihood of requiring surgery for a thyroid nodule decreased ~50%, from 65–70 to 35–40%, with a concomitant decrease in the number of thyroidectomies performed in the United States and elsewhere (4) .

Although FNA is currently the best initial diagnostic test for evaluation of a thyroid nodule, FNA cannot discriminate between benign and malignant follicular thyroid tumors. Current estimates indicate that carcinomas of the thyroid are ultimately found in 10–20% of lesions read as follicular tumors by FNA (5 , 6) . Patients seen with follicular thyroid lesions are advised to undergo surgery, generally a hemithyroidectomy, to provide an accurate diagnosis and direct additional treatment. Those who ultimately prove to have a carcinoma are frequently advised to undergo a second operation, completion thyroidectomy. In essence, patients have to decide preoperatively whether to undergo thyroid lobectomy or total thyroidectomy based on inadequate clinical information.

Thus, the current algorithms for managing a patient with a thyroid nodule deemed a follicular lesion by FNA are confusing and seemingly arbitrary. There is a clear need to develop more accurate initial diagnostic tests for thyroid nodules, particularly for those nodules classified as follicular lesions on initial cytopathological review, and potentially to direct subsequent treatment as well. Herein, we show that molecular analysis of follicular thyroid nodules by microarray analysis allows differentiation of benign and malignant tumors and may prove useful in directing both the initial treatment, as well as follow-up.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tissue Samples.
Primary tumor tissues were obtained at time of surgery from patients with a preliminary diagnosis of follicular thyroid tumor. All tumor samples were obtained with permission of and in accordance with the guidelines of the respective Institutional Review Boards. A pathologist dissected the tumor tissue, and a 2-mm cube was obtained, snap frozen in liquid nitrogen, and stored at -80°C. Histological classification was confirmed, and diagnosis of adenoma or carcinoma was obtained from the final pathology report. The clinical and histological features are summarized in Table 1Citation .


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  		Table 1 Patient data, diagnosis

 
RNA Purification, Labeling, and Hybridization.
Frozen tissues were homogenized by sonication in Trizol reagent (Invitrogen, Carlsbad, CA). Total RNA was prepared according to the manufacturer’s protocol. Integrity of the RNA was assessed by spectrophotometry. Twenty-four follicular thyroid tumors were analyzed in all by oligonucleotide microarray (GeneChip Hu95 array; Affymetrix, Santa Clara, CA). The initial training set included 12 follicular adenomas and 7 follicular carcinomas. Subsequently, 5 follicular tumors of undisclosed diagnosis and 2 minimally invasive carcinomas were analyzed as the test set. The Hu95 array contains oligonucleotides representing >12,000 known genes. All procedures were performed according to the instructions from Affymetrix. Briefly, first-strand cDNA was synthesized from 5 µg of total RNA with T7 (dT)24 primer. Second-strand synthesis was carried out using Escherichia coli polymerase DNA ligase, and RnaseH was added to the reaction. The cDNA was purified and subjected to in vitro transcription for 5 h at 37°C. Fragmented cRNA was made in 5x fragmentation buffer at 94°C for 35 min and was biotin labeled. Labeled RNA was hybridized to Affymetrix oligonucleotide arrays at 45°C overnight. An aliquot of each sample was first hybridized to an Affymetrix Test Chip array to determine sample quality as outlined by the manufacturer. All samples were of good quality and hybridized to Affymetrix Hu95 GeneChips. Arrays were washed and stained with streptavidin-phycoerythrin three times. Chips were scanned in a Hewlett Packard ChipScanner (Affymetrix) to detect hybridization signals.

Data Analysis.
The data were analyzed using GeneChip Expression Analysis software (Affymetrix). The intensity of each probe set of the array was captured, and expression values were calculated. To determine the quantitative expression level, the average differences representing the perfectly matched versus the mismatched for each gene-specific probe were calculated. The data were normalized to account for variability in hybridization for probe pairs and other hybridization artifacts. The analysis designates whether a transcript is reliably detected (present) or not detected (absent).

Data analysis was performed to identify genes that were differentially expressed between the adenoma and carcinoma groups. Data from the 12 adenomas and 7 carcinomas that comprised the training set were used. The minimally invasive tumors were not included in the original training set because they behave differently than most follicular carcinomas. First, the data were screened to identify signals counted as present by the Affymetrix software. Second, signals with at least 2-fold differences in expression were identified because it has been established that a 2-fold or greater change is significant and accurate (7) . These results were screened with a nonparametric t test, with the P set at <0.01. One hundred five genes were identified as differentially expressed and were used as a gene list for cluster analysis. Data were exported to GeneSpring (Silicon Genetics, Redwood City, CA), which was used for unsupervised hierarchical clustering and statistical analysis. Cluster analysis was used to group the tumors based upon their similarities measured across expression of 105 genes.

Evaluation of Unknown Samples.
Once the hierarchical cluster analysis was established using gene expression profiles of differentially expressed genes in 17 tumors, the same analysis was performed on 5 follicular tumors with investigators blinded to the final diagnosis. The unknown specimens were obtained from a different institution than the tumors used to create the cluster analysis. These tumors were also collected by an Institutional Review Board-approved protocol. Gene profiles for the 105 differentially expressed genes of the 5 tumors were used to include these tumors to the test set. Additionally, the two minimally invasive follicular carcinomas were entered into the test set cluster.

Semiquantitative RT-PCR.
To verify the results obtained from the Affymetrix chip hybridization, 5 genes, which showed robust, >3-fold overexpression and for which primers were readily available, were chosen. One µg of total RNA was reverse transcribed with oligo(dT) primer. A 2-µl aliquot of the cDNA was used for PCR. The primers and PCR conditions are listed in Table 2Citation . Products were electrophoresed on an agarose gel and visualized by ethidium bromide under UV light.


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  		Table 2 PCR conditions and primers

 
Protein Purification and Western Blotting.
Frozen tissue was thawed in ice-cold homogenization buffer containing 150 mM NaCl, 50 mM Tris-buffered saline (pH 7.4), 10% glycerol, 1% Triton-X, 2 mM EGTA, 2 mM MgCl2, 1 mM diethyldithiocarbamate, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml leupeptin, 10 µg/ml aprotinin, 5 µg/ml pepstatin, 3 mM hydrogen peroxide, 50 mM sodium fluoride, 1 mM sodium orthovandate, and 10 mM sodium molybdate. Tissues were homogenized using a glass-on-glass tissue homogenizer. Homogenates were centrifuged at 11,750 x g for 10 min at 4°C to remove the particulate material. The protein concentration of the supernatant was measured using the Lowry protein assay kit.

Immunoblot analysis for EMMPRIN was performed. Fifty µg/lane of protein from tissue were loaded on a 10% SDS-PAGE gel; after transfer, the membrane was blocked in 3% BSA and incubated overnight with primary antibody. ß-Actin was used as an internal control.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Differentially Expressed Genes.
To determine genes differentially expressed in follicular carcinoma and adenoma, the levels of gene expression for the two groups were compared. One hundred five genes were differentially expressed in adenoma and carcinoma. Fifty-nine genes were up-regulated in carcinoma, whereas 49 genes were up-regulated in adenoma. The list of genes differentially expressed is outlined in Table 3Citation Citation .


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  		Table 3 Gene list

 

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  		Table 3A Continued

 
Two-Way Clustering.
The dendrogram displays the length and subdivision of the branches, which correlated to the relatedness of the thyroid tumors. Two distinct groups of tumors are apparent in this two-dimensional analysis, suggesting that the tumors can be divided into two types on the basis of the expression level of these 105 genes (Fig. 1)Citation . Notably, all of the samples in the top cluster had a pathologic diagnosis of follicular adenoma.



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  		Fig. 1. Gene cluster 17. Dendrogram of cluster analysis of 12 follicular adenomas and 7 follicular carcinomas based upon the pattern of expression of 105 differentially expressed genes. Red indicates relative high expression; blue indicates low levels of expression.

 
Diagnosis of Unknown Samples.
Five additional follicular tumor samples were obtained, all of which had the diagnosis undisclosed to the investigators. Gene expression analysis and subsequent cluster analysis identified 4 adenomas and 1 carcinoma (Fig. 2)Citation . Release of the pathologic diagnosis to the investigators revealed that the diagnosis predicted by clustering was correct in all 5 cases. Interestingly, the two minimally invasive carcinomas clustered with the follicular adenomas.



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  		Fig. 2. Gene cluster 19 + unknowns. Dendrogram of cluster analysis of 17 follicular tumors, plus 5 unknown samples (U1–5) and 2 minimally invasive carcinomas (C5*, C9*) based upon the pattern of expression of 105 differentially expressed genes. Red indicates relative high expression; blue indicates low levels of expression.

 
Corroboration of Gene Expression.
We validated the differential expression of 5 genes identified in this study by semiquantitative PCR on 19 of 24 tumors analyzed. One of these genes has been previously associated with thyroid carcinomas (met), and the remainder are not known to be involved in the molecular pathogenesis of follicular thyroid tumors. For each gene tested, the level of expression by RT-PCR correlated with the data obtained by microarray analysis (Fig. 3)Citation .



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  		Fig. 3. Semiquantitative PCR. Verification of carcinoma and adenoma-specific gene expression of ADM (adrenomedullin), ENPP2 (autotaxin), BSG (EMMPRIN), MET (c-met), and transforming growth factor ßII receptor by RT-PCR. Primers specific for the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase were used as controls. Samples A1–A10, adenomas, samples C1–C9 carcinomas, and C5* and C9* are minimally invasive carcinomas.

 
Additionally, differential expression of the protein EMMPRIN was confirmed by immunoblot (Fig. 4)Citation . The expression of EMMPRIN is greater in the follicular carcinomas than in the follicular adenomas.



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  		Fig. 4. Immunoblot. The differential expression of EMMPRIN was confirmed by Western blot. Fifty µg of protein were loaded/lane. The first four samples (left) are from follicular adenomas, the next four (right) are from follicular carcinomas.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Accurate preoperative diagnosis of thyroid nodules has been a goal of thyroid researchers and clinicians for decades. The widespread introduction of FNA > 20 years ago changed the management of thyroid nodules substantially and resulted in a significant decrease in rates of thyroidectomy for benign thyroid nodules (4) . Recent advances in molecular biology have yet to translate into more refined preoperative diagnosis and management of thyroid nodules and, in particular, follicular neoplasms of the thyroid. The data presented here suggest that follicular adenomas can be reliably distinguished from follicular carcinomas by molecular analysis. Furthermore, we have identified new genes that might be useful in the distinction of benign and malignant follicular tumors.

Follicular adenomas and carcinomas are two closely related neoplasms, with potentially markedly different clinical outcomes. Our current understanding of the molecular steps leading to a malignant phenotype in follicular tumors is limited. Previous studies have suggested a number of possibly important genetic alterations, including expression of galectin-3, met/HGF receptor, reactivation of telomerase, and PAX-8/peroxisome proliferator-activated receptor{gamma} fusion translocation (12, 13, 14, 15) . However, none of these molecular changes have translated into clinically useful markers to differentiate benign and malignant tumors to date. We turned to gene expression profiling in an attempt to identify new genes responsible for the differences in biological behavior between follicular adenomas and carcinomas.

Of the 105 genes identified with significantly different expression levels between adenomas and carcinomas, most have not been previously described as important in the molecular pathogenesis of thyroid carcinoma. We selected 6 genes for additional analysis to validate the microarray expression data. These genes were chosen because their expression profiles were among the most significantly different between adenomas and carcinomas. Of the 6 genes analyzed, we confirmed differential gene expression in 4 genes expressed preferentially in carcinomas, and 2 genes expressed preferentially in adenomas compared with carcinomas. One of the 4 genes, the met gene, has been previously reported to be overexpressed in papillary and follicular thyroid carcinoma (16) . Recently, Huang et al. (17) demonstrated overexpression of met in papillary thyroid carcinoma by microarray analysis.

A recent investigation into genes differentially regulated in metastatic versus nonmetastatic follicular carcinomas identified EMMPRIN as a marker for metastasis (18) . EMMPRIN is a cell surface glycoprotein of human tumor cells and stimulates neighboring fibroblasts to produce expression of several matrix mettaloproteinase (19) . EMMPRIN has been associated with enhanced expression in invasive human tumors. Zucker et al. (20) demonstrated that overexpression of EMMPRIN by transfection of the MDA-MB-436 breast cancer cell line with greatly increased its tumorigenicity and invasiveness in vivo.

The two remaining genes that we found to be overexpressed in follicular carcinomas, autotaxin and adrenomedullin, have not been previously analyzed in thyroid carcinomas, although they have been recognized as potential markers of carcinogenesis in other solid tumors. Autotaxin was originally isolated as a tumor motility-stimulating protein and is a member of the nucleotide pyrophosphatase and phosphodoiesterase enzyme family (21) . It is overexpressed in several human cancers such as melanoma, hepatocellular carcinoma, and neuroblastoma (22) . Recent work has revealed that it also has angiogenic properties and can stimulate the proliferation of several cancer cell lines (22 , 23) .

Adrenomedullin was isolated from pheochromocytoma and has recently been shown to play a role in cancer cell growth and survival (24) . It is abundantly expressed in tumor cell lines of epithelial origin (lung, breast, colon ovary, and prostate; Ref. 10 ). Furthermore, a clinical study performed on patients with ovarian carcinoma revealed an association with adrenomedullin expression and poor prognosis (25) .

Additional insight into the biological behavior of minimally invasive carcinomas may be provided by examination of the differences in expression of the 105 genes in these tumors. We elected not to include the minimally invasive tumors in the original training set because of their unusually benign behavior for a cancer. Thus, it is noteworthy that these tumors were clustered with the adenomas because the clinical outcome for patients with minimally invasive carcinomas is much more similar to adenomas than invasive carcinomas. It is also interesting to note the expression of autotaxin and adrenomedullin by PCR in these tumors. The pattern of expression is unlike the angioinvasive carcinomas, rather, they resemble more closely the adenomas.

Molecular classification of tumors is an emerging technology that will undoubtedly change the way patients are managed (26 , 27) . Follicular lesions of the thyroid are one group of neoplasms that may benefit greatly from molecular analysis as a part of the work-up. It is possible to determine the level of gene expression by PCR on RNA isolation from as few as 10 cells isolated as part of the FNA biopsy (28) . A recent study has examined this technique for preoperative diagnosis of medullary thyroid carcinoma (29) .

A clearer understanding of the nature of a follicular neoplasm may allow physicians and surgeons to more accurately advise patients as to the necessity for surgery, as well as the extent of surgery. This could result in a decrease in thyroid surgery for nodules predicted to be benign on molecular analysis, as well as appropriate comprehensive surgery for nodules predicted to be aggressive. Furthermore, decisions regarding postoperative adjuvant radioactive iodine treatment might be made with greater confidence. We are optimistic that future evaluation of thyroid nodules will include molecular analysis, in addition to the cytological diagnosis, obtained by thyroid FNA. The data presented here provide a host of new genes that should permit molecular analysis to become clinical reality in the future management of follicular thyroid tumors.


   ACKNOWLEDGMENTS
 
We thank Dr. Jenny Z. Xiang and Xianchun Huang of the Microarray Core Facility at Weill Medical College of Cornell University for assistance with performing the microarrays and helpful discussions.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Funded by the G. Tom Shires Faculty Scholar Award. Back

2 To whom requests for reprints should be addressed, at New York Presbyterian Hospital-Cornell University, Room F-2024, 525 East 68 Street, New York, NY 10021. Phone: (212) 746-5130; Fax: (212) 746-8771; E-mail: tjfahey{at}mail.med.cornell.edu Back

3 The abbreviations used are: FNA, fine needle aspiration; RT-PCR, reverse transcription-PCR; EMMPRIN, extracellular matrix metalloproteinase inducer. Back

Received 8/12/02; revised 12/30/02; accepted 12/30/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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