Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers.
J Clin Endocrinol Metab
; 93(8): 3106-16, 2008 Aug.
Article
em En
| MEDLINE
| ID: mdl-18492751
ABSTRACT
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.
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Bases de dados:
MEDLINE
Assunto principal:
Neoplasias da Glândula Tireoide
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Carcinoma
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Receptores Proteína Tirosina Quinases
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Fosfatidilinositol 3-Quinases
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Sistema de Sinalização das MAP Quinases
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Proteínas Proto-Oncogênicas c-akt
Limite:
Humans
Idioma:
En
Revista:
J Clin Endocrinol Metab
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos