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Cell cycle deregulation and TP53 and RAS mutations are major events in poorly differentiated and undifferentiated
Jaime Miguel Pita1, Inês Filipa Figueiredo, Margarida Maria Moura
1Unidade de Investigação em Patobiologia Molecular (J.M.P., I.F.F., M.M.M., V.L., B.M.C.) and Serviço de Endocrinologia (V.L.), Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal; and Centro de Estudos de Doenças Crónicas (J.M.P., I.F.F., M.M.M., V.L., B.M.C.), Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal.
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 (p21(CIP1)); CDKN1B (p27(KIP1)); CDKN2A (p14(ARF), p16(INK4A)); CDKN2B (p15(INK4B)); CDKN2C (p18(INK4C))], 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.
Insights
Anaplastic thyroid carcinoma (ATC) and poorly differentiated thyroid carcinoma (PDTC) treatments may be improved by targeting TP53, RAS, cell cycle regulators, and TGF-β pathways. These molecular alterations are key drivers in these aggressive thyroid cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Anaplastic thyroid carcinomas (ATCs) are highly lethal malignancies with limited effective treatment options.
- Understanding the molecular basis of ATC development is crucial for identifying new therapeutic strategies.
Purpose of the Study:
- To elucidate molecular alterations driving ATC development.
- To identify novel therapeutic targets for ATCs and poorly differentiated thyroid carcinomas (PDTCs).
Main Methods:
- Global gene expression profiling of ATCs.
- Validation of differentially expressed genes using quantitative RT-PCR.
- Analysis of mutations in key genes (RAS, BRAF, TP53, CTNNB1, PIK3CA, cell cycle inhibitors, PTEN, AXIN1) in ATCs and PDTCs.
Main Results:
- ATCs show underexpression of epithelial markers, upregulation of mesenchymal markers and TGF-β pathway genes, and overexpression of cell cycle genes.
- TP53 (42% ATC, 27% PDTC) and RAS (31% ATC, 18% PDTC) mutations are frequent and mutually exclusive.
- CDKN3 is upregulated and aberrantly spliced in ATCs and PDTCs.
- Mutations in PIK3CA, PTEN, and CDKI genes are observed in 10-20% of tumors.
Conclusions:
- TP53, RAS, cell-dependent kinase inhibitors (CDKIs), and the TGF-β pathway play significant roles in ATC and PDTC.
- These pathways represent promising therapeutic targets for treating aggressive thyroid cancers.
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