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Cell cycle deregulation and TP53 and RAS mutations are major events in poorly differentiated and undifferentiated thyroid carcinomas.

par Pita, Jaime Miguel ;Figueiredo, Inês Filipa;Leite, Valeriano;Cavaco, Branca Maria
Référence 26th Télévie’s Researchers Seminar (Brussels)
Publication Non publié, 2013-12-05

Poster de conférence

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Résumé :

Introduction: Tumours arising from thyroid follicular cells represent the most frequent endocrine malignancies. The great majority are well-differentiated carcinomas (WDTC), in general, successfully treated with surgery and radioactive iodine. On the other hand, poorly differentiated (PDTC) and, particularly, anaplastic (undifferentiated) thyroid carcinomas (ATC) are among the most lethal malignancies, for which most current therapeutic options have been ineffective.PDTC and ATC have been identified in co-existence with well-differentiated areas, suggesting that these aggressive tumors can arise from pre-existing indolent carcinomas. This process of dedifferentiation is supported by the detection, in PDTC and ATC, of BRAF and RAS genes mutations (commonly found in WDTC) in association with later acquired alterations in TP53, CTNNB1 (β-catenin) and PIK3CA genes.Global gene expression profiling have shown that compared with WDTC cases, PDTC and ATC exhibit deregulation of different cellular events, e.g., focal adhesion, cell motility, TGF-β signaling, chromosome segregation, cell cycle and proliferation.Aims: The present study aimed to elucidate the main molecular pathways and alterations contributing to PDTC and ATC development, and to identify novel therapeutic targets.Methods and results: Our previous comparison of the genome-wide expression between PDTC and WDTC/normal thyroid tissues, revealed deregulated molecular signatures mainly related to cell proliferation, poor prognosis, spindle assembly checkpoint and cell adhesion. In the present study, we profiled the global gene expression of 5 ATC, and validated differentially expressed genes by quantitative RT-PCR in an independent set of tumors. In a series of 48 tumors (26 ATC and 22 PDTC), we searched for pathogenic alterations in the hot-spot regions of RAS, BRAF, TP53, CTNNB1 (β-catenin) and PIK3CA genes. Additionally, in accordance with the deregulated pathways in ATC and PDTC, we sequenced the coding regions and splice sites of components involved in cell cycle [cyclin-dependent kinase inhibitors (CDKI): CDKN1A (p21CIP1); CDKN1B (p27KIP1); CDKN2A (p14ARF, p16INK4A); CDKN2B (p15INK4B); CDKN2C (p18INK4C)], cell adhesion (AXIN1) and proliferation (PTEN).Bioinformatic analysis of the expression profiling revealed that ATC were characterized by under-expression of epithelial and thyroid function components, upregulation of mesenchymal markers and genes from TGF-β pathway. In accordance, upregulation of the SNAI2 (SLUG) gene, a TGF-β-responsive mesenchymal factor, was validated. Similarly to PDTC, ATC also presented a deregulated over-expression of cell cycle and proliferation-related genes.The mutational analysis identified 20 ATC (77%) and 13 PDTC (59%) that harbored alterations in at least one of the 14 genes profiled. Most mutations were present in TP53 (42% of ATC; 27% of PDTC) or RAS (31% of ATC; 18% of PDTC) genes and these two alterations showed evidence of mutual exclusivity (P=0.0354). PIK3CA, PTEN and CDKI alterations were present in 20-30% of PDTC, and in 10-14% of ATC. BRAF, CTNNB1 and AXIN1 mutations, which have been frequently associated to PDTC and ATC, were rarely detected.Conclusions: Our work has pointed out the main pathways and alterations involved in the most aggressive thyroid carcinomas. This study identified crucial roles for TP53, RAS, CDKI, and TGF-β pathway, which may represent effective therapeutic targets for ATC and PDTC treatment.