CONTEXT: Genetic alterations in receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways have not been fully defined in anaplastic and follicular thyroid cancers [anaplastic thyroid cancer (ATC), follicular thyroid cancer (FTC)]. OBJECTIVE: The objective of the study was to explore a wide-range genetic basis for the involvement of these pathways in ATC. DESIGN: We examined mutations and copy number gains of a large panel of genes in these pathways and corresponding phosphorylation of ERK (p-ERK) and Akt. RESULTS: We found frequent copy gains of RTK genes, including EGFR, PDGFRalpha and -beta, VEGFR1 and 2, KIT, and MET and in PIK3Ca, PIK3Cb, and PDK1 genes in the PI3K/Akt pathway. Mutations of Ras, PIK3Ca, PTEN, and BRAF genes and RET/PTC rearrangements were common, whereas mutations in PDK1, Akt1, Akt2, and RTK genes were uncommon in ATC. Overall, 46 of 48 ATC (95.8%) harbored at least one genetic alteration, and coexistence of two or more was seen in 37 of 48 ATC (77.1%). These genetic alterations were somewhat less common in FTC. Genetic alterations that could activate both the PI3K/Akt and MAPK pathways were found in 39 of 48 ATC (81.3%). RTK gene copy gains were preferentially associated with p-Akt, suggesting their dominant role in activating the PI3K/Akt pathway. The phosphorylation of Akt was far more common than p-ERK in FTC, and both were relatively common and often coexisted in ATC. CONCLUSIONS: Genetic alterations in the RTKs and PI3K/Akt and MAPK pathways are extremely prevalent in ATC and FTC, providing a strong genetic basis for an extensive role of these signaling pathways and the development of therapies targeting these pathways for ATC and FTC, particularly the former.
CONTEXT: Genetic alterations in receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways have not been fully defined in anaplastic and follicular thyroid cancers [anaplastic thyroid cancer (ATC), follicular thyroid cancer (FTC)]. OBJECTIVE: The objective of the study was to explore a wide-range genetic basis for the involvement of these pathways in ATC. DESIGN: We examined mutations and copy number gains of a large panel of genes in these pathways and corresponding phosphorylation of ERK (p-ERK) and Akt. RESULTS: We found frequent copy gains of RTK genes, including EGFR, PDGFRalpha and -beta, VEGFR1 and 2, KIT, and MET and in PIK3Ca, PIK3Cb, and PDK1 genes in the PI3K/Akt pathway. Mutations of Ras, PIK3Ca, PTEN, and BRAF genes and RET/PTC rearrangements were common, whereas mutations in PDK1, Akt1, Akt2, and RTK genes were uncommon in ATC. Overall, 46 of 48 ATC (95.8%) harbored at least one genetic alteration, and coexistence of two or more was seen in 37 of 48 ATC (77.1%). These genetic alterations were somewhat less common in FTC. Genetic alterations that could activate both the PI3K/Akt and MAPK pathways were found in 39 of 48 ATC (81.3%). RTK gene copy gains were preferentially associated with p-Akt, suggesting their dominant role in activating the PI3K/Akt pathway. The phosphorylation of Akt was far more common than p-ERK in FTC, and both were relatively common and often coexisted in ATC. CONCLUSIONS: Genetic alterations in the RTKs and PI3K/Akt and MAPK pathways are extremely prevalent in ATC and FTC, providing a strong genetic basis for an extensive role of these signaling pathways and the development of therapies targeting these pathways for ATC and FTC, particularly the former.
Authors: Tanios Bekaii-Saab; Mitch A Phelps; Xiaobai Li; Motoyasu Saji; Laura Goff; John Sae Wook Kauh; Bert H O'Neil; Stephanie Balsom; Catherine Balint; Ryan Liersemann; Vasily V Vasko; Mark Bloomston; William Marsh; L Austin Doyle; Gilian Ellison; Michael Grever; Matthew D Ringel; Miguel A Villalona-Calero Journal: J Clin Oncol Date: 2011-04-25 Impact factor: 44.544
Authors: Joanna Klubo-Gwiezdzinska; Kirk Jensen; Andrew Bauer; Aneeta Patel; John Costello; Kenneth D Burman; Leonard Wartofsky; Matthew J Hardwick; Vasyl V Vasko Journal: J Endocrinol Date: 2012-05-29 Impact factor: 4.286
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