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

Abstract

Background: 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.

Summary: 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.

Conclusions: 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.

FIG. 1.

Schematic illustration of the highly simplified PI3K/Akt and MAP kinase pathways in thyroid cancer. Shown are the major elements in the two pathways. RTK, activated by growth factors, RET/PTC, and Ras can be coupled to both pathways. The remaining components regulate their respective pathways as described in the text. PTEN is a negative regulator of the PI3K/Akt pathway signaling. PI3K, phosphatidylinositol-3 kinase; RTK, receptor tyrosine kinase.

FIG. 2.

Diagrammatic illustration of a self-enhancement mechanism of the activation of PI3K/Akt pathway through PTEN methylation in thyroid cancer. In this model, activating genetic alterations, including gene copy gain or mutations in the PI3K/Akt pathway activate the pathway. This in turn leads to PTEN methylation, resulting in silencing of the PTEN gene. Loss of PTEN removes the inhibitory pressure of the pathway, forming a malicious self-activation cycle for the PI3K/Akt pathway signaling. This is seen most commonly in aggressive thyroid cancers, such as anaplastic thyroid cancer (ATC), as discussed in the text.

FIG. 3.

Schematic illustration of the PI3K/Akt and MAP kinase pathways driven by the increasing accumulation of genetic alterations in the progression from low-grade to high-grade thyroid cancers. In this model, primary genetic alterations in the MAP kinase pathway, such as the BRAF mutation, transform the thyroid cell into PTC. As the genetic alterations accumulate, particularly with those that can also activate the PI3K/Akt pathway, the cancer progresses into aggressive type, such as ATC. If primary genetic alterations, such as genetic or epigenetic silencing of PTEN, occur in the PI3K/Akt pathway, the thyroid cell is transformed into follicular thyroid tumors. As genetic alterations accumulate in this pathway, a follicular adenoma can progress into FTC when tumor invasion occurs, which can progress further into ATC when genetic alterations accumulate further, particularly if there are genetic alterations that can dually activate the PI3K/Akt and MAP kinase pathways, such as Ras mutations or genomic amplifications of the receptor tyrosine kinase genes. The increasing intensity of the gray tint in the circles represents increasing genetic alterations and the signaling pressure of the pathways in the progression from thyroid cells to benign thyroid tumors to differentiated thyroid cancers and to ATC. The figure is adapted from reference with permission. FTC, follicular thyroid cancer.