Cell Cycle Deregulation and TP53 and RAS Mutations Are Major Events in Poorly Differentiated and Undifferentiated Thyroid Carcinomas

JM Pita, IF Figueiredo, MM Moura… - The Journal of …, 2014 - academic.oup.com
JM Pita, IF Figueiredo, MM Moura, V Leite, BM Cavaco
The Journal of Clinical Endocrinology & Metabolism, 2014academic.oup.com
Background: Anaplastic thyroid carcinomas (ATCs) are among the most lethal malignancies,
for which there is no effective treatment. Objective: In the present study, we aimed to
elucidate the molecular alterations contributing to ATC development and to identify novel
therapeutic targets. Design: We profiled the global gene expression of five ATCs and
validated differentially expressed genes by quantitative RT-PCR in an independent set of
tumors. In a series of 26 ATCs, we searched for pathogenic alterations in genes involved in …
Background
Anaplastic thyroid carcinomas (ATCs) are among the most lethal malignancies, for which there is no effective treatment.
Objective
In the present study, we aimed to elucidate the molecular alterations contributing to ATC development and to identify novel therapeutic targets.
Design
We profiled the global gene expression of five ATCs and validated differentially expressed genes by quantitative RT-PCR in an independent set of tumors. In a series of 26 ATCs, we searched for pathogenic alterations in genes involved in the most deregulated cellular processes, including the hot spot regions of RAS, BRAF, TP53, CTNNB1 (β-catenin), and PIK3CA genes, and, for the first time, a comprehensive analysis of components involved in the cell cycle [cyclin-dependent kinase (CDK) inhibitors (CDKI): CDKN1A (p21CIP1); CDKN1B (p27KIP1); CDKN2A (p14ARF, p16INK4A); CDKN2B (p15INK4B); CDKN2C (p18INK4C)], cell adhesion (AXIN1), and proliferation (PTEN). Mutational analysis was also performed in 22 poorly differentiated thyroid carcinomas (PDTCs).
Results
Expression profiling revealed that ATCs were characterized by the underexpression of epithelial components and the up regulation of mesenchymal markers and genes from TGF-β pathway, as well as, the overexpression of cell cycle-related genes. In accordance, the up regulation of the SNAI2 gene, a TGF-β-responsive mesenchymal factor, was validated. CDKN3, which prevents the G1/S transition, was significantly up regulated in ATCs and PDTCs and aberrantly spliced in ATCs. Mutational analysis showed that most mutations were present in TP53 (42% of ATCs; 27% of PDTCs) or RAS (31% of ATCs; 18% of PDTCs). TP53 and RAS alterations showed evidence of mutual exclusivity (P = .0354). PIK3CA, PTEN, and CDKI mutations were present in 14%–20% of PDTCs, and in 10%–14% of ATCs. BRAF, CTNNB1, and AXIN1 mutations were rarely detected.
Conclusion
Overall, this study identified crucial roles for TP53, RAS, CDKI, and TGF-β pathway, which may represent feasible therapeutic targets for ATC and PDTC treatment.
Oxford University Press