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Annales d'Endocrinologie
Vol 64, N° 1  - février 2003
pp. 62-63
Doi : AE-02-2003-64-1-0003-4266-101019-ART17
Genetic alterations in differentiated thyroid cancer: what can be expected for gene expression profiling of thyroid carcinomas
 

M. Santoro [1], R. M. Melillo [1], F. Carlomagno [1], M. D. Castellone [1], D. Vitagliano [1], T. Guida [1], G. Vecchio [1], A. Fusco [1]
[1]  Centro di Endocrinologia ed Oncologia Sperimentale del C.N.R./Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università degli Studi “Federico II”, via S. Pansini 5, 80131 Napoli-Italy.

Thyroid cancer

Approximately 20.000 new cases of thyroid carcinoma are diagnosed each year in the United States. Four types of thyroid cancer comprise more than 98% of all thyroid maligancies: papillary (PTC) and follicular (FTC) thyroid carcinoma, both classified as differentiated carcinomas, undifferentiated (anaplastic) (UTC), and medullary thyroid carcinoma (MTC) [1], [5]. PTC accounts for about 80% of all thyroid cancers. Although the overall 5-year survival rate for PTC patients is very high, about 10% of patients develop an aggressive disease with local recurrences and distant metastases. The tumor features which predispose to such a malignant evolution remain unknown. Molecular markers of more aggressive tumors would be of great help in precisely defining prognosis and therapeutical decision making [9].

Molecular genetics

Well differentiated thyroid carcinomas are frequently associated to chromosome rearrangements generating fusion transforming proteins [12]. About 50% of PTCs harbour chromosomal inversions or translocations causing somatic rearrangements of RET and NTRK1 genes. Follicular carcinomas, but not adenomas, are associated with the t(2;3) (q13;p25) chromosomal translocation, leading to the fusion of the N-terminal part of PAX8 (a transcription factor expressed in thyroid cells) and the entire coding sequence of the peroxisome proliferator activated receptorγ (PPARγ) [8]. A number of other genes are targeted by somatic genetic alterations in thyroid tumors. The thyrotropin receptor (TSH-R) and the Gsα become oncogenic in a small fraction of toxic adenomas. Mutations in the small GTP-binding Ras proteins have been found with variable frequencies in follicular cell tumors: both benign adenomas and carcinomas [9]. The p53 tumor suppressor is selectively inactivated in thyroid anaplastic carcinomas. The PTEN tumor suppressor, a lipid and protein phosphatase, has been found deleted in a small fraction of thyroid adenomas and downmodulated in most carcinomas [9].

RET/PTC

Receptor protein tyrosine kinases (PTK) are characterized by a cytoplasmic domain that has intrinsic catalytic activity and is activated upon ligand binding. Ligand-induced dimerization juxtaposes the two catalytic domains allowing mutual transphosphorylation of tyrosine residues which are the key to downstream signaling. Phosphorylated tyrosines, in turn, propagate the signal by recruiting intracellular proteins which possess phosphotyrosine binding domains, such as SH2 and PTB domains. This permits the phosphorylation and the translocation to the plasma membrane of target enzymes, such as phospholipase Cγ, adapters, such as Grb2, or docking proteins, such as Shc, IRS-1, Gab, Dok and FRS2. Increasing numbers of human diseases involve mutations, misexpression or malfunctioning of receptor PTKs.

RET is a peculiar example of how a PTK can cause human tumors [7], [11]. At the germ line level, point mutations of RET are responsible for multiple endocrine neoplasia type 2. At the somatic level, gene rearrangements (RET/PTC) juxtaposing the TK domain of RET to the N-terminal portion of several unrelated proteins possessing dimerizing activity are found in PTCs [4], [13]. This causes constitutive enzymatic activation and oncogenic conversion of the receptor. Expression in cultured cell lines has demonstrated that RET/PTC alleles promote mitogenesis, apoptosis and de-differentiation of thyroid cells. Transgenic mice models have formally proven that they are able to initiate thyroid tumorigenesis [7]. At least 10 different RET/PTC versions, rearranged with different genes, have been reported so far. PTC-associated gene rearrangements potentiate the intrinsic tyrosine kinase activity of RET and, ultimately, RET downstream signaling events. Given its oncogenic ability and selective association with PTCs, RET/PTC oncogenes are attractive therapeutic targets as demonstrated by the recent discovery of a pyrazolo-pyrimidine, PP1, that inhibits RET/PTC oncoproteins with a half maximal inhibitor concentration of 80nM. PP1 blocked anchorage-independent growth and tumorigenicity in nude mice of NIH3T3 fibroblasts expressing RET/PTC [2].

Gene expression profiling of thyroid cancer

Recently developed genomic technologies will help obtaining global molecular profiles which should provide us with the ability of addressing fundamental questions such as whether a cancer is prone to metastasize, which are the different prognostic outcomes of tumors otherwise morphologically indistinguishable, whether we can be able to to detect tumors as early as possible, whether tumors are prone to acquire an angiogenic potential, whether we can predict different responses to therapy [3], [10]. These novel approaches are being used for the study of thyroid cancer. Huang and colleagues [6]recently reported an initial characterization of the expression profile of eight matched pairs of normal thyroid and PTC tissues. They found increased expression of at least 46 genes in most PTCs analysed, most of which encode adhesion molecules. This study provides the first example of the possibility of obtaining a molecular signature of papillary thyroid cancer. We have searched for genes involved in RET/PTC-mediated thyroid carcinogenesis with an alternative approach. Instead of using tissue samples we have focused on an in vitro model thyroid system. We have compared expression profiles of rat thyroid PC Cl 3 cells transfected with RET/PTC oncogenes with the parental counterpart by using commericially available oligonucleotide-based DNA arrays interrogating approximately 26.000 rat sequences. We found that at least 100 genes are induced by more than 5-fold in RET/PTC transformed cells. These genes encode protein products involved in signalling, apoptosis, cell proliferation, adhesion, invasion, metabolism, and inflammation. We are currently focusing on the analysis of the molecular pathways leading to RET/PTC-dependent up-regulation of these genes as well as the expression of these genes in thyroid tissue samples.

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