help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chiappetta, G.
Right arrow Articles by Fusco, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chiappetta, G.
Right arrow Articles by Fusco, A.
The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 1 364-369
Copyright © 2002 by The Endocrine Society

Other Original Articles

The RET/PTC Oncogene Is Frequently Activated in Oncocytic Thyroid Tumors (Hurthle Cell Adenomas and Carcinomas), but Not in Oncocytic Hyperplastic Lesions

Gennaro Chiappetta, Paolo Toti, Francesco Cetta, Ada Giuliano, Francesca Pentimalli, Ida Amendola, Stefano Lazzi, Mario Monaco, Luca Mazzuchelli, Piero Tosi, Massimo Santoro and Alfredo Fusco

Istituto Nazionale dei Tumori di Napoli (G.C., A.G., I.A., M.M.), Fondazione Senatore Pascale, 80131 Napoli, Italy; Istituto di Anatomia Patologica (P.Tot., S.L., P.Tos.), Università degli Studi di Siena, Nuovo Policlinico, 53100 Siena, Italy; Istituto di Clinica Chirurgica (F.C.), Università degli Studi di Siena, Nuovo Policlinico, 53100 Siena, Italy; Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche (F.P., I.A., M.S., A.F.), Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università di Napoli "Federico II," 80131 Naples, Italy; Institute of Pathology (L.M.), University of Bern, CH-3010 Bern, Switzerland

Address all correspondence and requests for reprints to: Alfredo Fusco, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli "Federico II", via Pansini 5, 80131 Naples, Italy. E-mail: afusco{at}napoli.com


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Hurthle cell adenomas and carcinomas, characterized by the presence of oncocytic cells, are unusual thyroid neoplasms, the treatment of which is still controversial. We analyzed specimens from 49 patients with oncocytic cell nodular lesions including 20 adenomas, 19 carcinomas, and 10 hyperplasias for RET/PTC (papillary thyroid carcinoma) activation, which is the most frequent genetic alteration in PTCs. RET/PTC activation was detected in a significant number of cases of Hurthle cell adenomas and carcinomas, but in 0 of 10 patients with hyperplastic nodules. In particular, the RET/PTC1 isoform was found in 7 of 12 adenomas and 4 of 7 carcinomas. These results would indicate that RET/PTC is a genetic event common to papillary carcinomas and to Hurthle cell neoplasias.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THYROID NEOPLASIAS DERIVING from the follicular cells include a broad spectrum of tumors with different phenotypes and variable clinical behaviors (1, 2, 3). Molecular events involved in thyroid carcinogenesis include activation of the RET/PTC (papillary thyroid carcinoma) and the TrkA tyrosine kinase receptors in papillary carcinomas, activation of the ras genes by point mutation in follicular carcinomas, and inactivation of the p53 gene in anaplastic tumors (4, 5). Recently, a fusion between Pax8 and PPAR{gamma}1, following a t(2;3) (q13; p25) chromosomal translocation, has been described in five of eight thyroid follicular carcinomas (6).

RET/PTCs are chimeric genes generated by the fusion of the RET tyrosine kinase domain with the 5'-terminal region of other genes. Several different RET/PTC isoforms have been identified so far that differ in the fusion partner (7, 8, 9, 10, 11, 12, 13, 14, 15). RET/PTC1 and RET/PTC3 are the most prevalent RET/PTC variants (4, 5). In RET/PTC1 and RET/PTC3, the fusion occurs with the H4 (or D10S170) gene (4, 5) and RFG gene, respectively (10). A chromosomal inversion [inv ( 10) (q11.2q21)] accounts for the generation of RET/PTC1, whereas a cytogenetically undetectable paracentric inversion within 10q11.2 accounts for RET/PTC3 activation (4, 5). All of the genes fused to RET are ubiquitously expressed and therefore able to drive the expression of truncated forms of RET in thyroid follicular cells, which normally do not express it. RET/PTC oncogenes are able to transform differentiated thyroid cells in culture (16, 17). Moreover, transgenic mice carrying the RET/PTC1 and RET/PTC3 oncogene, under the transcriptional control of the thyroid-specific thyroglobulin promoter, developed PTCs (18, 19, 20), strongly indicating a pivotal role of this oncogene in the pathogenesis of human thyroid papillary carcinomas.

Two very sensitive techniques, i.e. immunohistochemistry and RT-PCR, have been set up to analyze RET/PTC activation in paraffin-embedded tissues. By these techniques, it has been found that RET/PTC is activated in classical papillary carcinomas, but not in follicular, poorly differentiated, and anaplastic carcinomas (21). Moreover, it has been proposed that RET/PTC activation may represent an early event in the generation of papillary carcinomas because it is present in occult thyroid papillary carcinomas (22, 23, 24, 25) and in papillary hyperplastic lesions (Tallini, G., G. Chiappetta, M. Santoro, A. Fusco, and J. Rosai, unpublished observations). A correlation has been found between RET/PTC activation and radiation-induced tumors. In fact, a higher percentage of RET/PTC3 was found in solid-follicular tumors arising in children after the Chernobyl power plant explosion (26, 27, 28, 29, 30, 31, 32, 33, 34). Conversely, RET/PTC1 activation is prevalent in PTCs after therapeutic irradiation (35, 36).

Recently, RET/PTC activation has been found in a subtype of differentiated tumors such as the trabecular (37, 38). Moreover, a recent study highlighted RET/PTC activation in Hurthle cell thyroid tumors including adenomas and carcinomas (39). Hurthle cell tumors of the thyroid are unusual neoplasms characterized by the presence of oncocytes (also called Askanazy or oxyphil cells), which are large polygonal cells with hyperchromatic, often bizarre, nuclei and an eosinophilic granular cytoplasm. Such a peculiar aspect of the cytoplasm is related to the presence of a large number of mitochondria, or in rare cases, to richness in granular endoplasmic reticulum. Some investigators believe that Hurthle cell tumors are distinctive from other follicular cell neoplasms (3), whereas others consider them to be subtypes of follicular lesions (40). Moreover, because differential histological diagnoses between benign lesions and their malignant counterparts may be very difficult and in some cases almost impossible, total thyroidectomy has been suggested as the treatment of choice in patients with Hurthle cell neoplasms (40).

The aim of this work was to analyze RET/PTC activation in a larger number of patients with oncocytic lesions, including adenomas, carcinomas, and hyperplastic nodules. Here, we report RET/PTC1 activation in a large number of patients with Hurthle cell adenomas and carcinomas. Conversely, 0 of 10 patients with hyperplastic nodules showed RET/PTC activation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Human thyroid tissues

Forty-nine cases of nodular oxyphilic cell lesions of the thyroid were collected from the files of the Institutes of Pathology at the Universities of Berne and Siena. Specimens obtained from surgery were fixed immediately at room temperature in 4% formaldehyde in PBS (pH 7.4), embedded in paraffin, and processed for histology. Hematoxylin-eosin and Gomori-stained preparations were reviewed independently by two pathologists. Only nodules composed exclusively or predominantly (>90%) of follicular cells exhibiting oncocytic features were included in the study. Oncocytes were defined by the presence of an abundant granular acidophilic cytoplasm. In all cases, the oxyphilic cells were immunoreactive to an antimitochondrial antibody (41, 42). On the basis of qualitative histological criteria, nodules were assigned to one of the three categories, i.e. hyperplasias, adenomas, and carcinomas. In particular, the lack of a fibrous capsule identified hyperplastic nodules. Adenomas were characterized by the presence of a complete fibrous capsule with compression of the surrounding thyroid tissue. Tumors were only registered as carcinomas if they exhibited unquestionable invasion through the full thickness of the capsule and/or into extracapsular blood vessels. Two cases among carcinomas were Hurthle cell variants of papillary carcinoma. Cases of tumors in which a differential histological diagnosis between benign and malignant was questionable were excluded. Consensus on the classification of tumors was reached in every case. In particular, there were 20 patients with adenomas, 19 with carcinomas, and 10 with hyperplastic nodular lesions.

Immunohistochemistry

Paraffin sections (3–4 µm) were deparaffinized, placed in a solution of absolute methanol and 0.3% hydrogen peroxide for 30 min, and then washed in distilled H2O, washed with PBS, and treated with diluted blocking serum for 20 min. Then, slides were incubated overnight at 4 C in a humidified chamber with affinity-purified antibodies specific for the RET tyrosine-kinase domain diluted 1:100 in PBS. The slides were subsequently incubated with biotinylated goat antirabbit IgG for 20 min (Vectostain ABC kits, Vector Laboratories, Inc., Burlingame, CA) and then with premixed reagent ABC (Vector Laboratories, Inc.) for 20 min. Immunostaining was performed by incubating the slides in diaminobenzidine (DAB-DAKO, DAKO Corp., Carpinteria, CA) solution containing 0.06 mM diaminobenzidine and 2 mM hydrogen peroxide in 0.05% PBS (pH 7.6) for 5 min. After chromogen development, the slides were washed, counterstained with hematoxylin, dehydrated with alcohol and xylene, and mounted with coverslips using a permanent mounting medium (Permount). Anti-RET polyclonal rabbit antibodies were raised in our laboratory and directed against the tyrosine kinase domain of RET expressed as recombinant glutathione-S-transferase fusion protein. They were affinity-purified by sequential chromatography first on RET and then on glutathione-S-transferase-coupled agarose columns. The characterization and specificity of these antibodies has been described elsewhere (21, 25).

To verify the oncocytic nature of thyroid cells, we used the monoclonal antibody AC 113–1 (BioGenex Laboratories, Inc., San Ramon, CA), which recognizes a mitochondrial protein. For enhanced antigen retrieval, deparaffinized sections were subjected to pressure cooking in 1 mM EDTA (pH 8.0) for 5 min. The alkaline phosphatase antialkaline phosphatase technique was applied.

RT-PCR analysis

RNA extraction from paraffin-embedded samples was performed following a published procedure (25). Briefly, single 6- to 8-µm tissue sections, cut from paraffin blocks, were stirred for 20 min in 1.5-ml tubes with 1 ml xylene. After centrifugation, the pellet was washed with 0.5 ml ethanol and air-dried. The dried pellet was resuspended in 200 µl of 6 mg/ml proteinase K (Sigma, St. Louis, MO), 1 M guanidinium thiocyanate, 25 mM 2-mercaptoethanol, 0.5% Sarkosyl, 20 mM Tris-HCl (pH 7.5), and incubated at 45 C for 6 h. Then, RNA was extracted with one sample equivalent volume of 70% phenol/30% chloroform, and the aqueous supernatant was transferred to a 0.5-ml tube containing 2 µg glycogen. After one volume of isopropanol was added, the supernatant was precipitated at -20 C overnight. After centrifugation for 15 min at 12,000 x g in an Eppendorf (Westbury, NY) microcentrifuge, the pellet was washed with 70% ethanol and air-dried. RT and subsequent PCR amplification were performed as previously reported (8). The sequences of the forward primers used were: RET/PTC1, 5'-ATTGTCATCTCGCCGTTC-3' [nucleotides 196–214 (7)]; RET/PTC2, 5'-TATCGCAGGAGAGACTGTGAT-3' [nucleotides 483–503 (8)]; RET/PTC3, 5'-AAGCAAACCTGCCAGTGG-3' [nucleotides 697–714 (10)]. The sequence of the reverse primer (synthesized according to the RET tyrosine-kinase sequence) was: 5'-TGCTTCAGGACGTTGAAC-3' [nucleotides 543–561 (7)]. One fifth of the RNA was reverse transcribed using the reverse primer and, after the addition of the forward primer, subjected to 40 cycles of PCR with a thermal cycler (Perkin-Elmer Cetus, Perkin-Elmer Corp., Norwalk, CT) (94 C for 30 min, 55 C for 2 h, and 72 C for 2 h). The product of the reaction was analyzed on a 2% agarose gel and hybridized with an RET probe covering the tyrosine-kinase domain. The human aldolase-specific primers were: forward primer, 5'-CGCAGAAGGGGTCCTGGTGA-3'; reverse primer, 5'-CAGCTCCTTCTTCTGCTGCGGGGTC-3'. The aldolase amplified product was 171 bp (43).

Statistical analysis

For pairwise comparisons of categorical data between groups, the Fisher’s exact test (2-tailed) was used (statistical software package, MedCalc, Mariakerke, Belgium). A two-sided P value less than 0.05 was considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Immunohistochemistry combined with RT-PCR analysis has been used to analyze RET/PTC activation on paraffin-embedded tumoral samples (21, 25). Immunohistochemistry was used because it is known that the RET proto-oncogene is normally expressed in neural crest-derived tissues but not in thyroid follicular cells; conversely, its rearranged forms are expressed in thyroid neoplastic cells, as a consequence of a change of the promoter. Therefore, RET expression in thyroid neoplasms was considered to reflect its activation. Recently, it has been shown that the product of RET proto-oncogene is present in some PTCs (44). However, this does not invalidate the use of the immunohistochemistry in the analysis of RET/PTC activation in thyroid carcinomas. In fact, the lack of RET expression in thyroid tumor samples surely does exclude the activation of the RET/PTC oncogene. Therefore, RET expression was analyzed in paraffin-embedded specimens from 49 patients with thyroid nodules showing oncocytic metaplastic cells. Results obtained by immunohistochemistry are summarized in Table 1Go. RET staining was observed in 9 of 19 Hurthle carcinoma samples and in 12 of 20 adenoma samples. Conversely, no oncocytic hyperplastic nodule expressed the RET protein. RET expression was significantly more frequently found in the neoplastic tissues than in hyperplastic nodules (12 of 20 vs. 0 of 10, P = 0.0016; and 9 of 19 vs. 0 of 10, P = 0.011, respectively). Some representative results of this analysis are shown in Fig. 1Go. No positivity is shown in normal thyroid tissue (Fig. 1AGo), in one hyperplastic nodule (Fig. 1BGo), and in one negative Hurthle cell adenoma (Fig. 1DGo), whereas a cytoplasmic staining is observed in one Hurthle cell adenoma and one carcinoma sample after staining with antibodies vs. the RET protein (Fig. 1, C and EGo, respectively). The specificity of the reaction was validated by the absence of staining when carcinoma samples were analyzed with antibodies preincubated with the peptide against which antibodies were raised (Fig. 1GGo). No positivity was also observed in the absence of the primary antibodies (Fig. 1HGo).


View this table:
[in this window]
[in a new window]
  		Table 1. RET/PTC oncogene activation in oncocytic thyroid tumors

 


View larger version (148K):
[in this window]
[in a new window]
  		Figure 1. Immunohistochemical analysis of RET expression in thyroid Hurtle tumors. Paraffin sections from thyroid adenomas and carcinomas were analyzed by immunohistochemistry using antibodies raised against a specific RET peptide. A, Immunostaining of a normal thyroid tissue (x200). No immunoreactivity was observed. B, Immunostaining of a hyperplastic thyroid lesion (x200). No immunoreactivity was observed. C, Immunostaining of a Hurthle cell adenoma (x200). Strong cytoplasmic staining was observed. D, Immunostaining of a negative Hurthle cell adenoma (x400). No immunoreactivity was observed. E, Immunostaining of a Hurthle cell carcinoma (x200). A strong cytoplasmic positivity was observed. F, Same as E, but at a higher magnification (x400). G, Immunostaining of a Hurthle cell carcinoma (the same case as E) with the RET antibodies preincubated with the peptide against which antibodies were raised (x400). No immunoreactivity was observed. H, Immunostaining of a Hurthle cell carcinoma (the same case as E) in the absence of the primary antibodies (x200). No immunoreactivity was observed.

 
Immunohistochemical analysis was subsequently combined with RT-PCR, using specific primers for the most frequent isoforms, i.e. RET/PTC1, RET/PTC2, and RET/PTC3. Unfortunately, due to the small amount of RNA extracted from paraffin-embedded specimens, RT-PCR analysis was performed in few cases. Results of this analysis are shown in Table 1Go and Fig. 2Go. Seven of 12 patients with adenomas (58.3%) and 4 of 7 patients with Hurthle cell carcinomas (57.1%) were positive for RET/PTC1. There were no patients with RET/PTC2 and RET/PTC3 activation. On the contrary, 0 of 10 hyperplastic nodules showed positivity for RET/PTC1, RET/PTC2, or RET/PTC3 activation, in accordance with findings obtained by immunohistochemistry. RET/PTC1 activation was significantly more frequent in the neoplastic tissues than in hyperplastic nodules (7 of 12 vs. 0 of 10, P = 0.0053; and 4 of 7 vs. 0 of 10, P = 0.0147, respectively).



View larger version (40K):
[in this window]
[in a new window]
  		Figure 2. RT-PCR analysis of the RET/PTC1, RET/PTC2, and RET/PTC3 expression in Hurthle neoplastic lesions. Top, RNAs extracted from thyroid samples (1 2 3 4 5 6 7 8 ) were amplified with RET/PTC1- and RET/PTC3-specific primers, subjected to electrophoretic separation on a 2% agarose gel, and hybridized with an RET probe. The first two lanes show as a positive control an RT-PCR performed on RNA extracted from tumors induced in nude mice by RET/PTC1-transfected NIH 3T3 cells. The lanes indicated with (-) show a PCR amplification of RNAs that was not reverse transcribed before PCR amplification, as a control that results were due to amplification of RNA and not to contaminating DNA. The same RNAs were subjected to RT-PCR amplification using aldolase primers. The products of the amplification were run on a 2% agarose gel and hybridized with an aldolase probe. Lanes 1 and 2, RNAs extracted from Hurthle hyperplasias; lanes 3–6, RNAs extracted from Hurthle adenomas; lanes 7–10, RNAs extracted from Hurthle carcinomas. Bottom, a schematic diagram of the H4-RET fusion and the position of the RET/PTC1 primers used in this study.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this report, we demonstrate the activation of RET/PTC in Hurthle cell neoplasias including adenomas and carcinomas by a combination of immunohistochemistry and RT-PCR analysis. By immunohistochemical analysis, 12 of 20 adenomas and 9 of 19 carcinomas were positive for RET expression. By RT-PCR, we detected the expression of RET/PTC1 chimeric transcript in 7 of 12 adenomas and 4 of 7 carcinomas. Conversely, no RET/PTC activation was found in 10 oncocytic hyperplastic nodules. Some samples that were positive for immunohistochemical analysis were negative for RT-PCR. This could be due to the variable expression of the RET proto-oncogene, as already described (44), or to the activation of an RET/PTC isoform other than PTC 1, 2, and 3. It is worth noting that these positive samples gave rise to an amplified product when primers specific for the catalytic domain of RET were used (data not shown). Conversely, four adenomas and three carcinomas that were negative for the detection of the RET protein by immunohistochemistry were also negative for RET/PTC activation and for the expression of the RET tyrosine kinase domain by RT-PCR (data not shown).

Interestingly, in the present study only activation RET/PTC1 isoform has been found, whereas in previous studies (39) RET/PTC2 and RET/PTC3 isoforms were also found. Different technical procedures, i.e. cycles of amplification as well as different geographical origin of the samples, may account for the different results. However, the present results, even though they show significant differences in comparison with previous reports on the same subject, confirm that the Hurthle cell adenoma and carcinoma share a molecular genetic alteration, namely RET/PTC activation, that is common to papillary carcinomas. It can be suggested that the presence of other genetic alterations may confer the typical characteristics and aspect of the Hurthle cells to the thyroid cells. Interestingly, in the present study we also analyzed specimens from 10 patients with hyperplastic nodules with oncocytic metaplasia. All of them were negative for RET/PTC activation. This suggests that RET/PTC activation may be considered a secondary event in Hurthle cell adenomas or carcinomas, i.e. subsequent to the occurrence of genetic alterations determining oncocytic metaplasia. Interestingly, Hurthle cell adenomas and carcinomas showed a fairly similar rate of RET/PTC activation. From these data, it might be suggested that Hurthle cell neoplasias are always malignant lesions, often with a favorable clinical outcome, like PTCs, which actually share the same genetic alteration. Such a working hypothesis may also explain why 1) a differential histological diagnosis between benign and malignant tumors in many cases is almost impossible; 2) tumors totally benign at histological examination may give origin to distant metastasis; and 3) oncocytic malignant tumors are thought to be more aggressive, because only the most aggressive forms are currently categorized as malignant.

In conclusion, the present study confirms that RET/PTC is not restricted to the PTC, but can also occur in Hurthle cell adenomas and carcinomas, probably as a secondary event. These results also indicate that Hurthle cell neoplastic lesions share the same genetic alterations as PTCs.


   Acknowledgments
 
We thank the Associazione Partenopea per la Ricerche Oncologiche for its support.


   Footnotes
 
This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (Progetto Speciale Oncosoppressori), the Progetto Finalizzato "Biotecnologie" of the Consiglio Nazionale delle Ricerche, Telethon projects E611 and E1123, the Ministero dell’Università e della Ricerca Scientifica e Tecnologica projects "Terapie antineoplastiche innovative" and "Piani di Potenziamento della Rete Scientifica e Tecnologica", and the "Ministero della Sanità".

Abbreviations: PTC, Papillary thyroid carcinoma.

Received May 7, 2001.

Accepted October 9, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Hedinger C, Williams ED, Sobin LH 1989 The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer 63:908–911[CrossRef][Medline]
  2. Williams ED 1979 The aetiology of thyroid tumours. Clin Endocrinol Metab 8:193–207[CrossRef][Medline]
  3. Rosai J, Carcangiu ML, DeLellis RA 1992 Tumors of the thyroid gland. In: Atlas of tumor pathology, 3rd series, fascicle 5. Washington, DC: Armed Forces Institute of Pathology
  4. Pierotti MA, Bongarzone I, Borello MG, Greco A, Pilotti S, Sozzi G 1996 Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells. Genes Chromosomes Cancer 16:1–14[CrossRef][Medline]
  5. Fusco A, Santoro M 1997 Human thyroid carcinogenesis. Forum 7:214–229
  6. Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, Fletcher JA 2000 Pax8-PPARgamma1 fusion in oncogene human thyroid carcinoma. Science 289:1357–1360[Abstract/Free Full Text]
  7. Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A, Vecchio G 1990 PTC is a novel rearranged form of the RET proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:557–563[CrossRef][Medline]
  8. Santoro M, Carlomagno F, Hay ID, Herrmann MA, Grieco M, Melillo R, Pierotti MA, Bongarzone I, Della Porta G, Berger N, Peix JL, Paulin C, Fabien N, Vecchio G, Jenkins RB, Fusco A 1992 RET oncogene activation in human thyroid neoplasms is restricted to the papillary carcinoma subtype. J Clin Invest 89:1517–1522
  9. Bongarzone I, Monzini N, Borrello MG, Carcano C, Ferraresi G, Arighi E, Mondellini P, Della Porta G, Pierotti MA 1993 Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of RET tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A. Mol Cell Biol 13:358–366[Abstract/Free Full Text]
  10. Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Grieco M, Pierotti MA, Vecchio G, Fusco A 1994 Molecular characterization of RET/PTC3: a novel rearranged version of the RET proto-oncogene in a human thyroid papillary carcinoma. Oncogene 9:509–516[Medline]
  11. Bongarzone I, Butti MG, Coronelli S, Borrello MG, Santoro M, Mondellini P, Pilotti S, Fusco A, Della Porta G, Pierotti MA 1994 Frequent activation of RET protooncogene by fusion with a new activating gene in papillary thyroid carcinomas. Cancer Res 54:2979–2985[Abstract/Free Full Text]
  12. Fugazzola L, Pierotti MA, Vigano E, Pacini F, Vorontsova TV, Bongarzone I 1996 Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer. Oncogene 13:1093–1097[Medline]
  13. Klugbauer S, Demidchik EP, Lengfelder E, Rabes HM 1998 Detection of a novel type of RET rearrangement (PTC5) in thyroid carcinomas after Chernobyl and analysis of the involved RET-fused gene RFG5. Cancer Res 58:198–203[Abstract/Free Full Text]
  14. Klugbauer S, Rabes HM 1999 The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas. Oncogene 18:4388–4393[CrossRef][Medline]
  15. Corvi R, Berger N, Balczon R, Romeo G 2000 Protein, nucleotide RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma. Oncogene 31:4236–4242
  16. Santoro M, Melillo RM, Grieco M, Berlingieri MT, Vecchio G, Fusco A 1993 The TRK and RET tyrosine kinase oncogenes cooperate with ras in the neoplastic transformation of a rat thyroid epithelial cell line. Cell Growth Differ 4:77–84[Abstract]
  17. De Vita G, Zannini M, Cirafici AM, Melillo RM, Di Lauro R, Fusco A, Santoro M 1998 Expression of the RET/PTC1 oncogene impairs the activity of TTF-1 and Pax-8 thyroid transcription factors. Cell Growth Differ 9:97–103[Abstract]
  18. Jhiang SM, Cho JY, Ryu KY, DeYoung BR, Smanik PA, McGaughy VR, Fischer AH, Mazzaferri EL 1996 Targeted expression of the RET/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137:375–378[Abstract]
  19. Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G, Picone A, Portella G, Santelli G, Vecchio G, Fusco A 1996 Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12:1821–1826[Medline]
  20. Powell Jr DJ, Russell J, Nibu K, Li G, Rhee E, Liao M, Goldstein M, Keane WM, Santoro M, Fusco A 1999 The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res 58:5523–5528[Abstract/Free Full Text]
  21. Tallini G, Santoro M, Helie M, Carlomagno F, Salvatore G, Chiappetta G, Carcangiu ML, Fusco A 1998 RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res 4:287–294[Abstract/Free Full Text]
  22. Soares P, Fonseca E, Wynford Thomas D, Sobrinho-Simoes M 1998 Sporadic RET-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms? J Pathol 185:71–78[CrossRef][Medline]
  23. Sugg SL, Zheng L, Rosen IB, Freeman JL, Ezzat S, Asa SL 1996 RET/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential? J Clin Endocrinol Metab 81:3360–3365[Abstract]
  24. Lam AK, Montone KT, LiVolsi VA 1998 RET oncogene activation in papillary thyroid carcinoma: prevalence and implications on the histological parameters. Hum Pathol 29:565–568[CrossRef][Medline]
  25. Viglietto G, Chiappetta G, Martinez-Tello FJ, Fukunaga FH, Tallini G, Rigopoulou D, Visconti R, Mastro A, Santoro M, Fusco A 1995 RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene 11:1207–1210[Medline]
  26. Ito T, Seyama T, Iwamoto KS, Mizuno T, Tronko ND, Komissarenko IV, Cherstovoy ED, Satow Y, Takeichi N, Dohi K, Akiyama M 1994 Activated RET oncogene in thyroid cancers of children from areas contaminated by Chernobyl accident. Lancet 344:259
  27. Fugazzola L, Pilotti S, Pinchera A, Vorontsova TV, Mondellini P, Bongarzone I, Greco A, Astakhova L, Butti MG, Demidchik EP, Pacini F, Pierotti MA 1995 Oncogenic rearrangements of the RET proto-oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. Cancer Res 55:5617–5620[Abstract/Free Full Text]
  28. Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM 1995 High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident. Oncogene 11:2459–2467[Medline]
  29. Nikiforov Y, Rowland JM, Bove KE, Monfore Munoz H, Fagin JA 1997 Distinct patterns of RET rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 57:1690–1694[Abstract/Free Full Text]
  30. Smida J, Salassidis K, Hieber L, Zitzelsberger H, Kellerer AM, Demidchik EP, Negele T, Spelsberg F, Lengfelder E, Werner M, Bauchinger M 1999 Distinct frequency of RET rearrangements in papillary thyroid carcinoma of children and adults from Belarus. Int J Cancer 80:32–38[CrossRef][Medline]
  31. Alipov G, Ito M, Prouglo Y, Takamura N, Yamashita S 1999 RET proto-oncogene rearrangement in thyroid cancer around Semipalatinsk nuclear testing site. Lancet 354:1528–1229[CrossRef][Medline]
  32. Thomas GA, Bunnell H, Cook HA, Williams ED, Nerovnya A, Cherstvoy ED, Tronko ND, Bogdanova TI, Chiappetta G, Viglietto G, Pentimalli F, Salvatore G, Fusco A, Santoro M, Vecchio G 1999 High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant. J Clin Endocrinol Metab 84:4232–4238[Abstract/Free Full Text]
  33. Santoro M, Thomas GA, Vecchio G, Williams GH, Fusco A, Chiappetta G, Pozcharskaya V, Bogdanova TI, Demidchik EP, Cherstvoy ED, Voscoboinik L, Tronko ND, Carss A, Bunnell H, Tonnachera M, Parma J, Dumont JE, Keller G, Hofler H, Williams ED 2000 Gene rearrangement and Chernobyl-related thyroid cancers. Br J Cancer 82:315–322[CrossRef][Medline]
  34. Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D, Klugbauer S 2000 Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-Chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res 3:1093–1103[Abstract]
  35. Bounacer A, Wicker R, Caillou B, Cailleux AF, Sarasin A, Schlumberger M, Suarez HG 1997 High prevalence of activating RET proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene 15:1263–1273[CrossRef][Medline]
  36. Learoyd DL, Messina M, Zedenius J, Guinea AI, Delbridge LW, Robinson BG 1998 RET/PTC and RET tyrosine kinase expression in adult papillary thyroid carcinomas. J Clin Endocrinol Metab 83:3631–3635[Abstract/Free Full Text]
  37. Papotti M, Volante M, Giuliano A, Fassina A, Fusco A, Bussolati G, Santoro M, Chiappetta G 2000 RET/PTC activation in hyalinizing trabecular tumors of the thyroid. Am J Surg Pathol 24:1615–1621[Medline]
  38. Cheung CC, Boerner SL, MacMillan CM, Ramyar L, Asa SL 2000 Hyalinizing trabecular tumor of the thyroid: a variant of papillary carcinoma proved by molecular genetics. Am J Surg Pathol 24:1622–1626[Medline]
  39. Cheung CC, Ezzat S, Ramyar L, Freeman JL, Asa SL 2000 Molecular basis of Hurthle cell papillary thyroid carcinoma. J Clin Endocrinol Metab 85:878–882[Abstract/Free Full Text]
  40. LiVolsi VA 1990 Surgical pathology of the thyroid. Philadelphia: Saunders
  41. Lazzi S, Spina D, Als C, Tosi P, Mazzucchelli L, Kraft R, Laissue JA, Cottier H 1999 Oncocytic (Hurtle cells) tumors of the thyroid: distinct growth patterns compared with clinicopathological features. Thyroid 9:97–104[Medline]
  42. Mazzuchelli L, Burckhardt E, Hirsiger H, Kappeler A, Laissue JA 2000 Interphase cytogenetics in oncocytic adenomas and carcinomas of the thyroid gland. Hum Pathol 31:854–859[CrossRef][Medline]
  43. Izzo P, Costanzo P, Lupo A, Rippa E, Borghese AM, Paolella G, Salvatore F 1987 A new human species of aldolase A mRNA from fibroblasts. Eur J Biochem 164:9–13[Medline]
  44. Bunone G, Uggeri M, Mondellini P, Pierotti MA, Bongarzone I 2000 RET receptor expression in thyroid follicular epithelial cell-derived tumors. Cancer Res 60:2845–2849[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J Ultrasound MedHome page
Z. V. Maizlin, S. M. Wiseman, P. Vora, J. M. Kirby, A. C. Mason, D. Filipenko, and J. A. Brown
Hurthle Cell Neoplasms of the Thyroid: Sonographic Appearance and Histologic Characteristics
J. Ultrasound Med., May 1, 2008; 27(5): 751 - 757.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
M. Santoro, R. M. Melillo, and A. Fusco
RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture.
Eur. J. Endocrinol., November 1, 2006; 155(5): 645 - 653.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
Z. Zhu, R. Ciampi, M. N. Nikiforova, M. Gandhi, and Y. E. Nikiforov
Prevalence of RET/PTC Rearrangements in Thyroid Papillary Carcinomas: Effects of the Detection Methods and Genetic Heterogeneity
J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3603 - 3610.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
J. W. B. de Groot, T. P. Links, J. T. M. Plukker, C. J. M. Lips, and R. M. W. Hofstra
RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors
Endocr. Rev., August 1, 2006; 27(5): 535 - 560.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
Y. E. Nikiforov
RET/PTC Rearrangement--A Link between Hashimoto's Thyroiditis and Thyroid Cancer...or Not
J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2040 - 2042.
[Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
F. Weber, L. Shen, M. A. Aldred, C. D. Morrison, A. Frilling, M. Saji, F. Schuppert, C. E. Broelsch, M. D. Ringel, and C. Eng
Genetic Classification of Benign and Malignant Thyroid Follicular Neoplasia Based on a Three-Gene Combination
J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2512 - 2521.
[Abstract] [Full Text] [PDF]

Home page
 INT J SURG PATHOLHome page
K. T. Mai, G. Elmontaser, D. G. Perkins, J. Thomas, and W. A. Stinson
Benign Hurthle Cell Adenoma with Papillary Architecture: A Benign Lesion Mimicking Oncocytic Papillary Carcinoma
International Journal of Surgical Pathology, January 1, 2005; 13(1): 37 - 41.
[Abstract] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. Sadetzki, R. Calderon-Margalit, B. Modan, S. Srivastava, and R. M. Tuttle
Ret/PTC Activation in Benign and Malignant Thyroid Tumors Arising in a Population Exposed to Low-Dose External-Beam Irradiation in Childhood
J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2281 - 2289.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
S L Asa
My approach to oncocytic tumours of the thyroid
J. Clin. Pathol., March 1, 2004; 57(3): 225 - 232.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
C. A. French, E. K. Alexander, E. S. Cibas, V. Nose, J. Laguette, W. Faquin, J. Garber, F. Moore Jr, J. A. Fletcher, P. R. Larsen, et al.
Genetic and Biological Subgroups of Low-Stage Follicular Thyroid Cancer
Am. J. Pathol., April 1, 2003; 162(4): 1053 - 1060.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
T. G. Kroll
Molecular Rearrangements and Morphology in Thyroid Cancer
Am. J. Pathol., June 1, 2002; 160(6): 1941 - 1944.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chiappetta, G.
Right arrow Articles by Fusco, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chiappetta, G.
Right arrow Articles by Fusco, A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals