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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 354-357
Copyright © 2003 by The Endocrine Society

Original Article

Detection of the PAX8-PPAR{gamma} Fusion Oncogene in Both Follicular Thyroid Carcinomas and Adenomas

Linda Cheung, Marinella Messina, Anthony Gill, Adele Clarkson, Diana Learoyd, Leigh Delbridge, John Wentworth, Jeanette Philips, Roderick Clifton-Bligh and Bruce G. Robinson

Cancer Genetics Unit, Kolling Institute (L.C., M.M., D.L., J.W., R.C.-B., B.G.R.), and Departments of Surgery (L.D.) and Pathology (A.G., A.C., J.P.), Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia

Address all correspondence and requests for reprints to: Prof. Bruce G. Robinson, Cancer Genetics Unit, Kolling Institute, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. E-mail: bgr{at}med.usyd.edu.au.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Chromosomal translocations encoding fusion oncoproteins are common in hematological malignancies, sarcomas, and papillary thyroid carcinomas. A recent study of follicular thyroid carcinomas reported a novel chromosomal translocation, t(2;3)(q13;p25), that fused the thyroid-specific transcription factor PAX8 with a nuclear receptor, peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}). Herein we report the detection of this putative oncoprotein in 6 of 17 (35%) follicular thyroid carcinomas as well as in 6 of 11 (55%) follicular thyroid adenomas. Concordant expression of protein was found in 91% of those tumors in which PAX8-PPAR{gamma} mRNA was detected by RT-PCR, whereas a further 20% of follicular tumors were positive for PPAR{gamma} immunohistochemistry alone. Our findings suggest that the PAX8-PPAR{gamma} fusion protein promotes differentiated follicular thyroid neoplasia, although it is not sufficient per se for carcinogenesis.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
A CRITICAL ISSUE in the management of thyroid neoplasia is the preoperative distinction between follicular thyroid carcinoma (FTC) and follicular thyroid adenoma (FTA). Discrimination of these subtypes of thyroid neoplasms on fine needle aspiration biopsy is not often possible. Thyroidectomy is performed for diagnostic evaluation in cytologically indeterminate cases, up to 80% of which will be benign on histological analysis (1, 2, 3). Recently, several promising molecular markers have been analyzed for their ability to discriminate between benign and malignant follicular tumors, including galectin-3 (4, 5, 6, 7, 8), thyroid peroxidase (9, 10, 11, 12), telomerase (13, 14, 15, 16), and p53 (17, 18, 19). However, with the possible exception of galectin-3, none of these markers has been shown to have the diagnostic accuracy required for routine clinical use.

Kroll et al. (20) reported that a chromosomal translocation fusing the thyroid transcription factor PAX8 and the nuclear receptor peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) was present in a significant proportion of follicular thyroid cancers, but not in benign thyroid lesions or papillary carcinomas. PAX8 is a critical regulator of thyroid differentiation, growth, and function. In contrast, PPAR{gamma} is a ligand-dependent nuclear transcription factor highly expressed in adipose tissue that is thought to be the principal target of the novel antidiabetic agents, the thiazolidinediones (21). It was therefore surmised that the upstream PAX8 promoter elements would be responsible for thyroid-specific expression of the fusion protein. Furthermore, they showed that the PAX8-PPAR{gamma} protein inhibited thiazolidinedione-induced gene trans-activation by wild-type PPAR{gamma}. It was concluded that PAX8-PPAR{gamma}-mediated transcriptional dysregulation might play a critical role in follicular thyroid carcinogenesis in a manner highly reminiscent of the well established oncogenic role for analogous fusion proteins that occur in acute promyelocytic leukemia (22).

In this study we examined follicular thyroid neoplasms for the presence of the PAX8-PPAR{gamma} rearrangement and the histological distribution of its protein product.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Follicular thyroid tumors were collected during the period from 1993–2001, and their use in this study depended upon the availability of sufficient tumor tissue and obtaining informed consent from each patient. The project was approval by the local ethics committee. We examined 17 FTCs and 11 FTAs for the expression of PAX8-PPAR{gamma} mRNA by RT-PCR. Histological sections of these tumors were examined by immunohistochemistry using a monoclonal antibody directed against PPAR{gamma}. Tumors were classified as benign or malignant according to WHO criteria (23); tumors with partial, but not full, thickness capsular invasion and without vascular invasion were classified as benign (24).

RNA isolation and RT-PCR

Total RNA was isolated from snap-frozen tumor samples with TRIzol reagent (Sigma-Aldrich, St. Louis, MO). cDNA was synthesized from 2 µg RNA with Superscript II reverse transcriptase (Invitrogen, Groningen, The Netherlands). PCR was performed with primers specific for sequences in exon 6 of PAX8 (5'-cgcggatccgcattgactcacagagca-3') and exon 1 of PPAR{gamma} (5'-ccggaattcgaagtcaacagtagtgaa-3') in a mixture containing 2 µl cDNA, 1 mM MgCl2, and Platinum Taq (Invitrogen). PCR conditions were 94 C for 10 sec, 60 C for 15 sec, and 70 C for 15 sec for 40 cycles. The integrity of the RNA was confirmed by simultaneous amplification of the ß2-microglobulin gene (forward primer, 5'-acccccactgaaaaagatga-3'; reverse primer, 5'-atcttcaaacctccatgatg-3') in the same PCR reaction. Amplification of PAX8-PPAR{gamma} cDNA variants containing PAX8 exons 1–6, 1–7, 1–7 plus 9, or 1–8, as previously described (20), was expected to generate products of 296, 417, 519, and 606 bp, respectively. PCR products were resolved by 5% acrylamide gel electrophoresis, and their sizes were determined by comparison with molecular weight markers (GeneScan-500 TAMRA, PE Applied Biosystems, Warrington, UK). RT-PCR products were subcloned after restriction digestion with BamHI and EcoRI, excision from 1.2% agarose gel, and ligation into pBluescript (Stratagene, La Jolla, CA). The identities of these inserts were verified by sequencing (data not shown). The expression of mRNA encoding the PAX8-PPAR{gamma} translocation was confirmed with repeat RT-PCR for each tumor.

Immunohistochemistry

Immunohistochemistry was performed on paraffin-embedded tumor sections. The tissues were sectioned onto positively charged slides (SuperFrost Plus, Menzel-Glaser, Freiburg, Germany) and deparaffinized with xylene and alcohol. Water bath antigen retrieval was performed at 97 C for 50 min in 10 mM citrate buffer (pH 6), followed by incubation for 60 min at room temperature with a monoclonal anti-PPAR{gamma} antibody E8 (SC-7273, Santa Cruz Biotechnology, Inc., Santa Cruz, CA) at concentration of 1:100. Immune complex detection was with LSAB-Plus (K690, DAKO Corp., Carpenteria, CA).

Statistical analyses

Characteristics of tumors positive or negative for the fusion product were compared by unpaired t test, and P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The expression of chimeric PAX8-PPAR{gamma} mRNA was detected in both FTCs and FTAs. Figure 1Go shows representative RT-PCR results from FTCs and FTAs together with the identity of each band detected on PAGE. Four mRNAs were identified that each contained a variable number of PAX8 exons fused with an invariant sequence in exon 1 of PPAR{gamma}. Notably, we identified a novel variant containing PAX8 exons 1–6 (Fig. 1Go, asterisk) in addition to three other variants previously described (20). Multiple variants were detected in each tumor from independent RT-PCR analyses (Table 1Go) and were often present in the same reaction (Fig. 1Go, lanes 1, 4, and 5). Paraffin-embedded tumor sections were stained with an anti-PPAR{gamma} monoclonal antibody. Figure 2Go shows strong anti-PPAR{gamma} signal within the nuclei of a representative FTC, whereas adjacent nonneoplastic thyroid tissue shows weak cytoplasmic staining.



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  		Figure 1. Presence and absence of multiple PAX8-PPAR{gamma} mRNA transcripts from FTC tumors 2, 12, 13, and 3 (lanes 1–4) and FTA tumors 2, 3, 5, and 11 (lanes 5–8). The sizes of fusion transcripts are shown on the left. *, The novel PAX8-PPAR{gamma} variant.

 

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  		Table 1. Detection of PAX8-PPAR{gamma} fusion transcript (RT-PCR) or protein (IHC) in FTCs or FTAs

 


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  		Figure 2. Follicular thyroid tissue stained with monoclonal anti-PPAR{gamma} antibody. Intense nuclear positivity in follicular carcinoma (right) with negative staining in adjacent normal gland (left) is shown.

 
The table summarizes the results of PAX8-PPAR{gamma} expression in follicular thyroid tumors together with their histopathological and patient characteristics. PAX8-PPAR{gamma} mRNA was found in 6 of 17 FTCs (35%) and 6 of 11 FTAs (55%). Concurrent detection of the fusion protein using an anti-PPAR{gamma} antibody was present in 92% of these RT-PCR-positive tumors. An additional 4 FTCs (24%) and 1 FTA (9%) were positive for protein expression alone, consistent with the previous study (20), and possibly due either to chromosomal translocation beyond the primers used to detect the translocated product or to an alternative (as yet unidentified) proximal fusion partner. FTAs that demonstrated anti-PPAR{gamma} staining were more likely to have microfollicular architecture and a thick capsule than those FTAs with negative immunohistochemistry. None of 4 FTCs with oncocytic features (known also as Hürthle cell carcinomas) demonstrated the fusion mRNA or protein. Tumors expressing PAX8-PPAR{gamma} were smaller than those negative for the fusion product (33 ± 15 vs. 47 ± 17 mm; P = 0.05), but did not differ with respect to vascular invasion, age, or gender.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The initial description of the PAX8-PPAR{gamma} translocation suggested that its presence might have been specific to FTCs (20). However, in our study PAX8-PPAR{gamma} mRNA and protein were detected in both benign and malignant follicular thyroid tumors. Furthermore, during preparation of this manuscript, two other groups also reported the occurrence of the PAX8-PPAR{gamma} fusion in follicular thyroid carcinomas and adenomas (25, 26). Marques et al. (25) examined 9 FTCs and 16 FTAs and found the fusion product by RT-PCR in 56% FTCs and 13% FTAs; 78% FTCs and 31% FTAs were positive by anti-PPAR{gamma} immunohistochemistry in their study. Conversely, Nikiforova et al. (26) examined 15 FTCs and 25 FTAs and found the fusion product by RT-PCR in 53% FTCs and 8% FTAs, all of which demonstrated strong diffuse nuclear staining for PPAR{gamma}. Together our combined results indicate that PAX8-PPAR{gamma} is likely to be an important and possibly early event in follicular thyroid tumorigenesis, but that it is either insufficient per se to promote carcinogenesis or that FTAs possess some other mechanism to suppress malignant transformation. An alternate possibility is that PAX8-PPAR{gamma}-expressing tumors classified as benign on the basis of histopathology are, in fact, noninvasive follicular carcinomas; larger studies will be required to determine the prognostic significance of detecting this putative oncoprotein in follicular lesions.

In our study benign lesions expressing PAX8-PPAR{gamma} were more likely to have a microfollicular pattern and a thick capsule, suggesting that detection of the PAX8-PPAR{gamma} product defines a distinct pathological subset of follicular thyroid tumors. Moreover, in our study none of the 4 FTCs with Hürthle cell or oncocytic characteristics demonstrated the fusion mRNA transcript or protein, and in another recent study the fusion protein was not detected in 12 Hürthle cell carcinomas or 12 Hürthle cell adenomas (26). There has been considerable speculation as to whether Hürthle cell tumors may be clinically and histologically distinct from other follicular neoplasms (27, 28, 29, 30). Our observation suggests that Hürthle cell tumors may also have a distinct molecular pathophysiology.

The immunohistochemistry and RT-PCR findings were highly concordant, but a small number of tumors were positive for protein expression alone, consistent with the previous studies (20, 25, 26). This observation may be explained by chromosomal translocation beyond the primers used to detect the translocated product, by the presence of an alternative (as yet unidentified) proximal fusion partner, or by overexpression of native PPAR{gamma}. Although PPAR{gamma} is not known to be expressed in normal thyroid (20, 31), in one recent study overexpression of native PPAR{gamma} was observed in human papillary thyroid carcinoma, and thiazolidinedione treatment of PTC cell lines was shown to inhibit tumor growth (31).

We have reported several variants of PAX8 within the PAX8-PPAR{gamma} fusion product that we and others (20, 25, 26) interpret to represent differential splicing of PAX8 mRNA in a manner consistent with that known to occur in wild-type PAX8 (32, 33). We have enumerated PAX8 exons according to Kozmik et al. (33), consistent with those reported by Kroll et al. (20) and Nikiforova et al. (26). We note that our novel variant encoding exons of PAX8 and PPAR{gamma} has recently been also reported by Marques et al. (25), albeit using differently numbered PAX8 exons as reported by Poleev et al. (32).

The fusion of a tissue-specific transcription factor (PAX8) with a ligand-activated nuclear receptor (PPAR{gamma}) is highly reminiscent of chromosomal translocations that occur in acute promyelocytic leukemia (34). This malignancy is commonly associated with reciprocal translocations involving the myeloid-specific promyelocytic leukemia or promyelocytic leukemia zinc-finger genes on chromosomes 15 and 11, respectively, with the retinoic acid receptor {alpha} gene on chromosome 17. The successful use of retinoic acid to treat acute leukemias containing the fusion promyelocytic leukemia-retinoic acid receptor {alpha} oncoprotein (35) raises the possibility that ligands for PPAR{gamma} may have an analogous role in treating follicular thyroid carcinomas that relapse after surgery or are resistant to radioiodine.


   Acknowledgments
 
We thank Dr. T. Kroll for his provision of a PAX8-PPAR{gamma} expression vector used to design positive controls for the RT-PCR, and Dr. D. Marsh for her helpful discussion.


   Footnotes
 
This work was supported by grants from The Leo and Jenny Cancer and Leukemia Foundation and the University of Sydney Cancer Research Fund.

L.C. was supported by a Royal North Shore Hospital Westpac postgraduate scholarship.

Abbreviations: FTA, Follicular thyroid adenoma; FTC, follicular thyroid carcinoma; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}.

Received July 22, 2002.

Accepted October 15, 2002.


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M. Xing, R. P. Tufano, A. P. Tufaro, S. Basaria, M. Ewertz, E. Rosenbaum, P. J. Byrne, J. Wang, D. Sidransky, and P. W. Ladenson
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T. Dwight, S. R. Thoppe, T. Foukakis, W. O. Lui, G. Wallin, A. Hoog, T. Frisk, C. Larsson, and J. Zedenius
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