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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 One Day Symposium on “Darwinian evolution and clonal heterogeneity in human cancer: biological and clinical implications” with Keynote Speaker Carlos Caldas sponsored by EACR (Oporto)
Publication Non publié, 2012-10-29

Poster de conférence

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Résumé :

Most thyroid carcinomas are well-differentiated and can be successfully treated. On the other hand, poorly differentiated (PDTC) and, particularly, anaplastic (undifferentiated) thyroid carcinomas (ATC) are among the most lethal malignancies, for which there is no effective treatment. Previously, we analysed PDTC genome-wide expression and found molecular signatures mainly related to cell proliferation, spindle assembly checkpoint and cell adhesion. The aim of this study was to further elucidate the molecular pathways/alterations contributing to PDTC and ATC development. We profiled the global gene expression in 5 ATC, and analysed the mutational status of RAS, BRAF, TP53, CTNNB1, PIK3CA genes, of components involved in cell cycle control [CDKN1A (p21CIP1); CDKN1B (p27KIP1); CDKN2A (p14ARF, p16INK4A); CDKN2B (p15INK4B); CDKN2C (p18INK4C)], and in the epithelial-to-mesenchymal transition (EMT) regulation (AXIN1), in 23 PDTC and 26 ATC. SNAI2 (SLUG) gene expression was also validated. ATC molecular signatures were mainly related to cell cycle/proliferation, thyroid metabolism and cell junctions. In particular, gene expression profiling and quantitative PCR revealed up-regulation of the TGF-β target, SNAI2 gene, which may be involved in the loss of epithelial/follicular morphology and increased mesenchymal properties. PIK3CA and CDKN2A somatic mutations were detected in 15% of PDTC, but were less common in ATC (<5%). Furthermore, BRAF and CTNNB1 mutations were detected in less than 5% of the tumours. Most somatic mutations were detected in TP53 (22% of PDTC; 42% of ATC) or RAS (17% of PDTC; 31% of ATC). Mutations in TP53 gene and mutations in RAS or BRAF genes showed evidence of mutual exclusivity (P=0.0193). Patients with TP53 and/or RAS mutations had significant lower survival than TP53 and RAS-negative patients (P<0.0338). Overall, analysis of PDTC and ATC, confirmed the involvement of TP53, RAS, and PIK3CA genes, and revealed the contribution of genes, such as CDKN2A, that participate in cell cycle regulation.