Jaime Miguel Pita1, Inês Filipa Figueiredo, Margarida Maria Moura, Valeriano Leite, Branca Maria Cavaco. 1. Unidade 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.
Abstract
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.
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.
Authors: Iñigo Landa; Tihana Ibrahimpasic; Laura Boucai; Rileen Sinha; Jeffrey A Knauf; Ronak H Shah; Snjezana Dogan; Julio C Ricarte-Filho; Gnana P Krishnamoorthy; Bin Xu; Nikolaus Schultz; Michael F Berger; Chris Sander; Barry S Taylor; Ronald Ghossein; Ian Ganly; James A Fagin Journal: J Clin Invest Date: 2016-02-15 Impact factor: 14.808
Authors: Soeren Latteyer; Vera Tiedje; Katharina König; Saskia Ting; Lukas C Heukamp; Lydia Meder; Kurt Werner Schmid; Dagmar Führer; Lars Christian Moeller Journal: Endocrine Date: 2016-10-01 Impact factor: 3.633
Authors: Irene M Min; Enda Shevlin; Yogindra Vedvyas; Marjan Zaman; Brian Wyrwas; Theresa Scognamiglio; Maureen D Moore; Weibin Wang; Susan Park; Spencer Park; Suraj Panjwani; Katherine D Gray; Andrew B Tassler; Rasa Zarnegar; Thomas J Fahey; Moonsoo M Jin Journal: Clin Cancer Res Date: 2017-10-12 Impact factor: 12.531