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PMID: 20578891 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Genetic alterations in the phosphatidylinositol-3 kinase/Akt pathway in thyroid cancer.

Thyroid : official journal of the American Thyroid Association ·Vol. 20 ·No. 7 ·2010-07-00 ·Pages 697-706

Xing M

Abstract

Aberrant activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway plays a fundamental role in thyroid tumorigenesis, particularly in follicular thyroid cancer (FTC) and aggressive thyroid cancer, such as anaplastic thyroid cancer (ATC). As the drivers of this process, many genetic alterations activating the PI3K/Akt pathway have been identified in thyroid cancer in recent years. This review summarizes the current knowledge on major genetic alterations in the PI3K/Akt pathway. These include PIK3CA mutations and genomic amplification/copy gain, Ras mutations, PTEN mutations, RET/PTC and PPARgamma/Pax8 rearrangements, as well as amplification/copy gain of PIK3CB, PDK1, Akt, and various receptor tyrosine kinase genes. Most of these genetic alterations are particularly common in FTC and many of them are even more common in ATC; they are generally less common in papillary thyroid cancer (PTC), in which the MAP kinase (MAPK) pathway activated by the BRAF mutation instead plays a major role. Methylation and, thus, epigenetic silencing of PTEN, a major negative regulator of the PI3K/Akt pathway, occurs in close association with activating genetic alterations of the PI3K/Akt pathway, constituting a unique self-enhancement mechanism for this pathway. Many of these genetic alterations are mutually exclusive in differentiated thyroid tumors, but with increasing concurrence from benign tumors to FTC to ATC. RET/PTC, Ras, and receptor tyrosine kinase could dually activate the PI3K/Akt and MAPK pathways. Most cases of ATC harbor genetic alterations in these genes or other genetic combinations that can activate both pathways. It is proposed that genetic alterations in the PI3K/Akt pathway promote thyroid cell transformation to FTC and that genetic alterations in the MAPK pathway promote cell transformation to PTC; accumulation of multiple genetic alterations that can activate both pathways promotes thyroid cancer aggressiveness and progression to ATC. Genetic alterations are common in the PI3K/Akt pathway in thyroid cancer and play a fundamental role in the tumorigenesis and progression of this cancer. This provides a strong basis for the emerging development of novel genetic-based diagnostic, prognostic, and therapeutic strategies for thyroid cancer.

MeSH Terms
Animals Epigenesis, Genetic Gene Amplification Gene Rearrangement Genetic Therapy Humans Mutation Phosphatidylinositol 3-Kinases/genetics,metabolism Precision Medicine/methods Prognosis Proto-Oncogene Proteins c-akt/genetics,metabolism Signal Transduction/genetics Thyroid Neoplasms/diagnosis,genetics,metabolism,therapy Thyroid Nodule/diagnosis,genetics,metabolism,therapy
Chemicals
Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Xing Mingzhao
Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. mxing1@jhmi.edu
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Article Info
Journal
Thyroid : official journal of the American Thyroid Association
Abbr.
Thyroid
ISSN
1557-9077
DOI
10.1089/thy.2010.1646
Email
mxing1@jhmi.edu
Published
2010-07-00
Pages
697-706
Language
English
Region
United States
NLM ID
9104317
PMCID
PMC2935335
Subset
IM
Grants
NCI NIH HHS · R01CA134225 · United States
External Links
PubMed source DOI: 10.1089/thy.2010.1646 PMC Full Text View journal details
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