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Thyroid
Thyroid. 2010 Jul; 20(7): 697–706.
PMCID: PMC2935335

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 PPARγ/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.

Introduction

As in many other human cancers, genetic alterations are the driving force for the tumorigenesis and pathogenesis of thyroid cancer, particularly those that occur in genes encoding for key players of major signaling pathways. Follicular epithelial cell–derived thyroid cancer accounts for >95% of all thyroid malignancies and can be divided histologically into papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), and anaplastic thyroid cancer (ATC). PTC can be further divided into several subtypes: conventional variant PTC (CPTC), follicular variant PTC (FVPTC), tall cell PTC (TCPTC), and a few other rare types. There is also poorly differentiated thyroid cancer (PDTC) that has a prognostic risk between DTC (including PTC and FTC) and ATC. The genetic background varies with these different types of thyroid cancers, and certain molecular signaling pathways are consequently preferentially altered in them. A prominent example of such genetic alterations is the oncogenic BRAF mutation in the Ras → Raf → MEK → ERK/MAP kinase pathway (MAPK pathway), which occurs preferentially and commonly in PTC, particularly CPTC and TCPTC, and some ATC (1,2). Other classical oncogenic genetic alterations in the MAPK pathway in thyroid tumorigenesis include RET/PTC and Ras mutations (36). In recent years, the importance of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway in thyroid tumorigenesis has been also widely recognized (7). Recent studies have particularly explored the genetic backgrounds for this role of the PI3K/Akt pathway. As a result, many important genetic alterations have been identified in this pathway in recent years, providing insights into the molecular mechanisms in thyroid tumorigenesis and bases for the development of novel genetic-based strategies for the management of thyroid cancer.

Signaling of the PI3K/Akt Pathway

The PI3K/Akt signaling pathway has long been known to play a fundamental role in the regulation of various cellular and molecular functions, including glucose uptake, cell growth and proliferation, cell motility, and survival. In the last 15 years, the role of this signaling pathway in human tumorigenesis and its value as a therapeutic target in human cancers have been extensively investigated (811). There are several classes of PI3Ks, among which class I is the best characterized and most important in human tumorigenesis. It consists of heterodimers of a regulatory subunit, commonly the p85 unit, and one of p110 catalytic subunits. Among the p110 subunits, the α-type (PIK3CA) and β-type (PIK3CB) are widely expressed in different tissues and play a particularly important role in human cancers. PIK3CA and PIK3CB belong to class IA that is activated by receptor tyrosine kinases (RTK) as well as some G-protein-coupled receptors. These p110 catalytic subunits contain a binding site for the regulatory subunit, through which signals can be integrated from membrane receptors and activate the catalytic subunits. Ras is a classical player in the MAPK pathway, but it also plays an important role in the signaling of the PI3K/Akt pathway. One mechanism for this function of Ras is through its interaction with the Ras-binding site in the p110 catalytic subunits of PI3K. Thus, Ras can dually activate the MAPK and PI3K/Akt pathways. As illustrated in Figure 1, a typical starting point of the PI3K/Akt pathway signaling is the various membrane growth factor receptors that contain RTK, including vascular epithelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), c-KIT, and c-MET. Activation of RTK by extracellular signals leads to the activation of the PI3K with resultant activated p110 catalytic subunit (e.g., PIK3CA), which in turn phosphorylates phosphatidylinositol-4,5-bisphosphate to produce phosphatidylinositol-3,4,5-trisphosphate (PIP3). The function of PIP3 in this signaling relay is to localize Akt to the cell membrane where Akt becomes phosphorylated and activated by the phosphoinositide-dependent kinases (PDK), most prominently PDK1. Akt is a Ser/Thr kinase and three types of its isoforms are found in human tissues—Akt-1, Akt-2, and Akt-3 (12). Activated Akt phosphorylates downstream protein effectors, among which is the mammalian target of rapamycin (mTOR), which has a well-established role in human cancers and, like Akt, is a prominent therapeutic target in today's cancer therapy designing (13). The amplified signaling cascade regulates a wide range of molecular and cellular functions, promotes cell proliferation, and inhibits cell apoptosis. A prominent negative regulator of the PI3K/Akt pathway signaling is the protein product of the gene for phosphatase and tensin homolog deleted on chromosome ten (PTEN). PTEN is a phosphatase that dephosphorylates PIP3 and thus terminates the signaling of the PI3K/Akt pathway (14,15). Given the antagonizing function of PTEN against the PI3K/Akt signaling, PTEN is a major human tumor suppressor and its genetic alterations, like those of other genes in the PI3K/Akt pathway, have serious consequences. Shown in Figure 1 are the key players in the molecular interplay in the PI3K/Akt pathway signaling that have been best characterized for their genetic alterations in thyroid cancer as will be each discussed in this review.

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 ...

Mutations and Genomic Amplifications/Copy Gain of the PIK3CA Gene in Thyroid Cancer

Genetic alterations of the PIK3CA gene have been widely reported in human cancer. Activating mutations in the PIK3CA gene were initially found in colorectal, gastric, breast, and ovarian cancers, and high-grade brain tumors, supporting the important oncogenic role of this gene in human tumorigenesis (16). PIK3CA mutation was subsequently explored in various differentiated thyroid tumors but found to be uncommon in them (17). In a subsequent extended study, PIK3CA mutations in exons 9 and 20 were found to occur in 23% of ATC (18). PIK3CA mutations were also found in several more recent studies in FTC and ATC with lower frequencies, around 10%–15% (1923). Similarly to the occurrence of BRAF mutation in PTC-derived metastases (24,25), PIK3CA mutation can occur in some cases of metastases derived from aggressive cancers, such as PDTC and ATC (23), consistent with the general distribution patterns of the two mutations in primary thyroid tumors. Overall, PIK3CA mutation can occur, particularly in PDTC and ATC and their recurrent/metastatic disease, but does not seem to be a major genetic event in thyroid cancer in general.

Amplification/genomic copy gain of the PIK3CA gene as an important oncogenic event is common in human cancers, including ovarian cancer in which PIK3CA amplification was initially discovered (26). Lack of common PIK3CA mutations in thyroid cancer, particularly DTC, promoted search for genetic amplification or copy gain of this gene in thyroid cancer. This led to the initial discovery of genetic copy gain of the PIK3CA gene with a high prevalence in thyroid cancer, particularly FTC and ATC, being 24% and 42% in the former and the latter, respectively (17,27). This common occurrence of PIK3CA copy gain in thyroid cancer was confirmed in several subsequent studies in different ethnic populations (1922,28). Fluorescent in situ hybridization studies demonstrated that this PIK3CA copy gain in thyroid cancer represented mainly genomic amplification of the PIK3CA gene (17,20). Several previous studies showed that the PIK3CA amplification was associated with overexpression of the PIK3CA protein (19) and phosphorylation of Akt (17,22), suggesting that this genetic alteration of the PIK3CA gene is functional and represents a relevant mechanism for the activation of the PI3K/Akt pathway in thyroid cancer. Association of PIK3CA amplification with increased PIK3CA protein expression and kinase activity or Akt phosphorylation was documented in many other human cancers, such as ovarian and uterine cervical cancers (26,29,30). In the Asian and American populations, PIK3CA amplification in thyroid cancer occurred mainly in FTC and ATC and uncommonly in PTC (17,19,21,22,27,28), which is consistent with the notion that the PI3K/Akt pathway plays a major role in the tumorigenesis of FTC and ATC, as opposed to the MAPK pathway that plays a major role in the tumorigenesis of PTC (5). In a Middle East population, PIK3CA amplification was found to be common also in PTC by both quantitative real-time polymerase chain reaction and fluorescent in situ hybridization analyses (20). The reason for this difference is not clear. PIK3CA amplifications could occur in benign thyroid adenoma (BTA), although with a low prevalence (17,19,28), suggesting a possible early role of this genetic alteration in thyroid tumorigenesis. Aberrant genomic copy number has long been known to be associated with transition from precancerous epithelial lesions to cancers (31). PIK3CA amplification represents such a genomic copy gain, as exemplified by its association with progression of dysplasia into invasive squamous cell carcinoma (32). A recent study showed that PIK3CA amplification was strongly associated with distant metastasis, lymph node metastasis, advanced tumor stage of nasopharyngeal carcinoma, and decreased patient survival (33). The occurrence of PIK3CA amplification in some cases of BTA raises the question whether these benign thyroid tumors could progress into malignancy if given sufficient time. There was a clear and progressive increase in the prevalence of PIK3CA amplifications from BTA to FTC and to ATC (19,28), which is consistent with a role of this genetic alteration in promoting the aggressiveness and progression of thyroid cancer.

Common Ras Mutations in Follicular Thyroid Tumors

Mutations in the three types of Ras genes—H-Ras, K-Ras, and N-Ras—are commonly seen in human cancers with a frequency, on average, of 30% (34,35). Ras mutations are also common in thyroid tumors, particularly in FVPTC (36), FTC (19,22,28,37,38), and PDTC (23,39), with a prevalence around 20%–40% in most series. Ras mutations are reported in PTC with a varying and generally low prevalence (40), reflecting varying compositions of FVPTC, CPTC, and TCPTC, with the latter two rarely harboring Ras mutations. Ras mutations are also frequently seen in BTA, with a collective prevalence of about 20% in a meta-analysis (37) and 26% in a recent large study (38). It is unclear whether Ras mutations with physiological expression in BTA are oncogenic and can convert the benign tumor into thyroid malignancy. In fact, when introduced into normal thyroid epithelial cells, an H-Ras mutant induced only well-demarcated and differentiated colonies with phenotype consistent with follicular adenoma (41) and cell proliferation without loss of differentiation (42). In a recent transgenic mouse study, conditional physiological expression of a K-Ras mutant alone in the thyroid gland failed to transform thyroid cells to thyroid cancer even after 1 year (43). It appears that additional genetic alterations are required to transform thyroid cells but Ras mutation alone, with physiological expression, cannot. Indeed, concurrent mutated Ras gene expression and PTEN deletion resulted in rapid development of aggressive FTC and animal death within weeks in transgenic mouse studies (43).

Ras is widely known for its classical role in the MAPK pathway signaling through interacting with the Raf kinase. As discussed above, Ras can also regulate the PI3K/Akt pathway by directly interacting with the Ras-binding site of p110 catalytic subunits of PI3K (44,45). Ras mutants could activate the PI3K/Akt pathway, which also required direct interaction with the Ras-binding site on the p110 catalytic subunits of PI3K, such as PIK3CA (46). Interestingly, in colon cancer, K-Ras mutant preferentially activated the MAPK pathway, whereas N-Ras mutant did not (47). It is not clear whether different types of Ras mutations exert different oncogenic roles by preferentially activating different signaling pathways in thyroid tumorigenesis. The most common type of Ras mutations in thyroid cancer is the N-Ras mutation in codon 61, with H- and K-Ras mutations, in either codon 12/13 or codon 61, being much less common. This is the pattern observed by many groups (19,22,23,28,3639 ), except for ones that showed that K-Ras mutation was the most common (48,49). The fact that Ras mutations occur particularly in FTC and FVPTC in which aberrant PI3K/Akt signaling is a major signaling abnormality whereas they rarely occur in CPTC and TCPTC in which the BRAF mutation-activated MAPK signaling dominates (1,2) is consistent with the expectation that Ras mutations are major activators of the PI3K/Akt pathway in thyroid tumors, particularly follicular tumors. Some studies demonstrated a good association of Ras mutations with the phosphorylation of Akt in thyroid cancer (20,22), consistent with an important role of Ras mutations in the activation of the PI3K/Akt pathway in this cancer.

Genetic and Epigenetic Alterations of the PTEN Gene in Thyroid Cancer

PTEN mutations are relatively uncommon in sporadic human cancers. Inactivating germline mutations of this gene are the main cause of Cowden syndrome (50), which is characterized with a propensity of patients to develop tumors, including thyroid tumors, particularly follicular thyroid tumors, including FTC. As discussed above, as a lipid phosphatase that degrades PIP3, PTEN normally antagonizes and terminates the signaling of the PI3K/Akt pathway. Given the importance of this negative regulation of the PI3K/Akt pathway by PTEN, Cowden syndrome provides a unique human model illustrating the oncogenic power of aberrant PI3K/Akt signaling in the tumorigenesis of follicular thyroid tumors. Somatic PTEN mutations also occur in thyroid cancers, particularly in FTC and ATC, although with a relatively low prevalence (19,22,28). Loss of heterozygosity or deletion of the PTEN gene is relatively common in thyroid tumors (51,52). The real extent of genetic abnormalities of the PTEN gene in sporadic thyroid cancer likely exceeds what is currently seen as multiple alteration sites of the gene exist, some of which may be missed in relatively limited genetic analyses in most studies.

An epigenetic inactivating mechanism through aberrant methylation of the PTEN gene also exists in various thyroid tumors, particularly FTC and ATC (5355). When quantitatively analyzed using quantitative real-time methylation polymerase chain reaction, PTEN methylation was found to be progressively and steadily increased from BTA to FTC and to ATC (55). Methylation of a gene is usually associated with its silencing (56). Therefore, methylation of PTEN in thyroid tumors, particularly in FTC and ATC, which showed the highest extent of this methylation (55), is consistent with the previously reported decreased or even absent PTEN expression in a subset of these cancers (57,58). Interestingly, PTEN methylation in thyroid tumors was found to be closely associated with classical activating genetic alterations in the PI3K/Akt pathway, including Ras mutation, PIK3CA mutation, PIK3CA amplification, and mutations of the PTEN gene itself in thyroid tumors (55). This is consistent with a previously proposed mechanistic model for the regulation of the PI3K/Akt pathway in thyroid tumors (55), as illustrated in Figure 2. In this model, activation of the PI3K/Akt pathway by its genetic alterations may activate the methylating system of the cell, which, in turn, causes hypermethylation and hence epigenetic silencing of the PTEN gene, effectively removing the terminating mechanism of the PI3K/Akt signaling. This represents a unique self-enhancing mechanism of the PI3K/Akt pathway. This mechanism may be particularly relevant in ATC as genetic alterations of the PI3K/Akt pathway and, correspondingly, PTEN methylation were shown to be particularly common in this aggressive cancer (55). The potentially and conceivably malicious nature of such a self-enhancing mechanism for the activation of the PI3K/Akt pathway signaling may contribute to the pathogenesis and aggressiveness of ATC. Thus, the oncogenic power of loss of PTEN seems to lie in its cooperation with other genetic alterations of the PI3K/Akt pathway in the tumorigenesis of thyroid cancer. This mechanism is consistent with the recent findings in a transgenic mouse model in which deletion of PTEN or physiological expression of a Ras mutant each alone did not cause thyroid cancer, but simultaneous introduction of the two genetic events caused aggressive thyroid cancer (43).

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 ...

RET/PTC as an Activator of the PI3K/Akt Pathway in Thyroid Tumors

RET/PTC represents a recombinant protein product from a chromosomal rearrangement with the combination of the 3′ portion of the RET gene and the 5′ portion of a partner gene (3,59). This recombination results in constitutive activation of the tyrosine kinase in RET. Among the more than 10 types of RET/PTC, which are mainly found in thyroid cancer, the most common and important types are RET/PTC1 and RET/PTC3. RET/PTC is an established oncogenic activator of the MAPK pathway. Several studies have suggested that RET/PTC is also involved in the signaling of the PI3K/Akt pathway. For example, transfection of thyroid cells with RET/PTC3 could increase Akt phosphorylation and PI3K/Akt signaling (60,61). RET tyrosine kinase could activate the PI3K/Akt pathway through binding of several proteins, including the p85 regulatory subunit of PI3K, to tyrosine 1062 of RET (62). The transforming ability of a mutant RET of MEN2A, which, like RET/PTC, had constitutive activation of the RET tyrosine kinase, required binding of the p85 regulatory subunit of PI3K to tyrosine 1062 of RET to activate PI3K (63). It is conceivable that RET/PTC activates the PI3K/Akt pathway through a similar mechanism. Other mechanisms for the involvement of RET/PTC in the signaling of the PI3K/Akt pathway may also involve direct phosphorylation and activation of PDK1 (64) and Akt (65) by RET/PTC. Therefore, RET/PTC is an important player in the deranged signaling of the PI3K/Akt pathway in thyroid tumorigenesis. This may be a particularly important mechanism in PTC of pediatric patients as most of these patients harbor RET/PTC (1,3,59). RET/PTC occurs in about 15%–20% of adult PTC patients and, presumably, also plays a role in the activation of the PI3K/Akt pathway in these patients. RET/PTC is generally found to be mutually exclusive with BRAF mutation in PTC (1). This is thought to be evidence supporting the notion that either of the two genetic alterations can sufficiently and oncogenically activate the MAPK pathway. However, some studies did also show coexistence of RET/PTC and BRAF mutation in PTC and ATC (22,6668). Coexistence of RET/PTC and BRAF mutation was found to be more common in recurrent PTC, suggesting that coactivation of the MAPK and PI3K/Akt pathway by coexistence of the two genetic alterations may have a special role in thyroid cancer aggressiveness as will be further discussed in the following section. Many studies also showed that RET/PTC could occur, with high prevalences, in benign thyroid tumors (6971) and Hashimoto's thyroiditis (7274). Hyalinizing trabecular tumors of the thyroid gland also frequently harbored RET/PTC (75), which is largely a benign thyroid tumor (76). Therefore, it appears that RET/PTC alone, under physiological expression, may not be sufficiently oncogenic and additional coexisting genetic alterations may be required for thyroid cell transformation.

Genetic Alterations in the RTK Genes and Other Genes in the PI3K/Akt Pathway in Thyroid Cancer

In addition to the several genes in the PI3K/Akt pathway discussed above, there are many other genes that are involved in the initiation or transduction of the signaling of the PI3K/Akt pathway. Genetic alterations of these genes have been reported with varying rates in human cancers (77,78). A recent study extensively investigated mutation and genomic copy gain of many of these genes in thyroid cancer, particularly FTC and ATC (22). These included RTK genes EGFR, PDGFRα and β, VEGFR1 and 2, c-MET, and c-KIT, as well as PDK1, Akt-1, Akt-2, and PIK3CB. Interestingly, although mutations were not common in these genes examined on selected exons, genomic copy gain, likely representing genomic amplifications, was common in most of these genes in thyroid cancer, particularly in ATC, up to 40%–45% for EGFR, PDGFRβ, and VEGFR1. Consistent with these results are the previous findings that many of these genes were overexpressed in thyroid cancer (79). Like the highly prevalent genetic copy gain of the PIK3CA found in this study and as discussed above, PIK3CB copy gain was also found to be common, with a prevalence of around 40% in both FTC and ATC. A relatively high prevalence of PTEN mutation of 17% was found in ATC. This study also analyzed Ras mutations, RET/PTC, and BRAF mutation and showed prevalences comparable to previous reports. Overall, virtually every case of FTC or ATC harbored at least one genetic alteration, and coexistence of two or more was seen in the majority of cases of ATC. Specifically, 93% of FTC and 96% of ATC harbored at least one genetic alteration, and coexistence of two or more was seen in 77% of ATC. Many of these genetic alterations were correlated with phosphorylation of Akt, suggesting that they functioned as activators of the PI3K/Akt pathway. This study provided a strong genetic basis for a fundamental and wide role of the aberrant PI3K/Akt pathway signaling in thyroid cancer, particularly FTC and ATC.

There are several other genetic alterations that can activate the PI3K/Akt pathway in thyroid tumors. One is the PPARγ/Pax8 rearrangement. This genetic event was initially identified in FTC (80) and latter also found in BTA (81). Through a dominant-negative inhibition mechanism, the protein product PPARγ/Pax8 can negatively affect Pax8. As the latter is normally an upregulator of PTEN expression (82), PPARγ/Pax8 can thus indirectly suppress expression of PTEN, leading to the activation of the PI3K/Akt signaling. The preponderance of PPARγ/Pax8 in follicular tumors, in which the PI3K/Akt pathway signaling dominates as discussed above, is consistent with the role of this recombinant protein in PI3K/Akt signaling. A recent study showed that Akt-1 mutation could also occur in thyroid cancer, but only in some cases of recurrent/metastatic cancers, suggesting that this is a relatively late genetic event during thyroid cancer progression (23). Interestingly, in a mouse model with a knock-in mutant TRβ gene, the TRβ mutant could directly interact with the p85 regulatory subunit of PI3K and activate the PI3K/Akt signaling in FTC that developed in these transgenic mice (83). This represents a novel mechanism for the activation of the PI3K/Akt pathway. It remains to be investigated whether this mechanism may occur in human thyroid cancer.

Accumulation of Genetic Alterations in the PI3K/Akt Pathway and Their Concurrence with Genetic Alterations in the MAPK Pathway in the Progression from Low-Grade to Aggressive Thyroid Tumors

Genetic alterations in the PI3K/Akt pathway have an interesting and oncogenically important distribution pattern in different thyroid cancer. Two studies on different ethnic populations demonstrated that the classical genetic alterations, including PIK3CA mutation and genetic copy gain, Ras mutations, and PTEN mutations, were mutually exclusive in DTCs, suggesting that any of these genetic alterations was a sufficient oncogenic event for the activation of the PI3K/Akt pathway in these thyroid cancers (19,28). These genetic alterations were far more common in FTC than in PTC, perfectly echoing hyper-phosphorylation of Akt and over-activation of the PI3K/Akt pathway preferentially occurring in FTC over PTC (84). Coexistence of these genetic alterations was occasionally seen in differentiated thyroid tumors but occurred commonly in ATC (19,22). There is a clear rise in the prevalence of these genetic alterations, either individually or concurrently, from BTA to DTC and to ATC, reaching an extremely high prevalence in ATC (19,22). These genetic data strongly support a role of aberrantly activated PI3K/Akt pathway in the development of aggressiveness of thyroid cancer, consistent with the finding of increased Akt phosphorylation particularly in invasive areas of thyroid cancer (85).

Many of the genetic alterations found in ATC could potentially activate both the MAPK and PI3K/Akt pathways, including RTK gene copy gain, RET/PTC, and Ras mutations. BRAF mutation that can activate the MAPK pathway commonly coexisted with genetic alterations that could activate the PI3K/Akt pathway (e.g., the PIK3CA copy gain) in ATC. Genetic alterations or their combinations that could activate both the MAPK and PI3K/Akt pathways were found in up to 81% cases of ATC (22). Common coexistence of BRAF mutation with RET/PTC, Ras mutations, PIK3CA mutation and amplification, Akt-1 mutation, and other genetic alterations that can activate the PI3K/Akt pathway have been recently also reported in other studies, mostly in aggressive cancers such as recurrent/metastatic cancers, PDTC, and ATC (20,23,49,68). In general, the PI3K/Akt pathway is commonly activated in FTC, whereas the MAPK pathway is commonly activated in PTC by their corresponding common genetic alterations, and the two pathways are commonly dually activated in aggressive thyroid cancer, such as metastatic/recurrent cancers and ATC. This is consistent with a recently proposed model in which genetic alterations in the PI3K/Akt pathway and MAPK pathway promote transformation of follicular thyroid cells to FTC and PTC, respectively, and accumulation of these genetic alterations and their concurrence in both pathways drive the aggressiveness and progression of DTC into aggressive thyroid cancer, such as ATC (19). This model is illustrated in Figure 3.

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, ...

Interestingly, this model seems to also be applicable to other human cancers, such as melanoma in which simultaneous activation of the PI3K/Akt pathway by silencing of PTEN and the MAPK pathway by expression of a BRAF mutant led to aggressive progression and metastasis of the tumor (86).

Clinical Implications

The genetic studies discussed above on the PI3K/Akt pathway in thyroid cancer have important diagnostic, prognostic, and therapeutic implications. Recent studies tested the diagnostic value of combinational use of several genetic alterations, including Ras mutation, RET/PTC, PPARγ/Pax8, and BRAF mutation in the diagnostic evaluation of thyroid nodules (38,87,88). This approach could increase the sensitivity of conventionally used diagnostic modalities for thyroid nodules and was thought to be particularly useful for thyroid nodules with indeterminate cytology. However, unlike BRAF mutation, which occurs only in thyroid cancer, Ras mutation, RET/PTC, and PPARγ/Pax8 can all also occur in BTA and even Hashimoto's thyroiditis with relatively high prevalences, although lower than cancer, as discussed in the previous sections. Consequently, the specificity of this diagnostic approach could be potentially problematic, and further studies are required to determine how this approach can be practically applied diagnostically. This is different than the prognostic molecular marker, BRAF mutation, which is associated with aggressiveness of PTC and can therefore be practically useful in guiding the risk stratification of PTC (1,2). In this sense, the combinational use of the mutation markers discussed above might be prognostically useful since Ras mutation, RET/PTC, and likely PPARγ/Pax8 predict a less aggressive course of thyroid cancer than the BRAF mutation (1,2).

Some of the genetic alterations in the PI3K/Akt pathway may also be prognostically useful in certain clinical settings. For example, N-Ras mutations were recently shown to be prevalent in PDTC and predict an increased mortality of this cancer (39). As discussed above, BRAF mutation has been well known to be associated with aggressiveness of PTC (1,2). A recent study demonstrated that coexistence of PIK3CA amplification with BRAF mutation conferred PTC a particularly high risk for aggressiveness, including large tumor size, metastasis, and recurrence of PTC (20), raising the possibility that the combination pattern of the two genetic markers could identify a subgroup of BRAF-mutation-positive PTC with a particularly high risk for aggressiveness.

The current knowledge of genetic alterations in the PI3K/Akt pathway has also opened the possibility for development of specific genetic-based therapeutic strategies targeting the PI3K/Akt pathway in thyroid cancer. BRAF-mutation-dependent response of thyroid cancer cells to MEK and BRAF mutant inhibitors has been well-documented and represents a good example of genetic-based targeting of the MAPK pathway in thyroid cancer (89,90). Similar dependence of thyroid cancer cells on genetic alterations in the PI3K/Akt pathway in response to Akt and mTOR inhibitors has been demonstrated recently (91), providing the first evidence that effective genetic-based targeting of the PI3K/Akt pathway is possible with certain drugs for thyroid cancer. As dual involvement of the MAPK and PI3K/Akt pathways driven by their respective and concurrently existing or shared genetic alterations is a fundamental mechanism in the tumorigenesis of aggressive thyroid cancers, such as ATC, targeting both pathways may be needed for effective treatment of these cancers. The two recent studies demonstrating synergism of MEK and mTOR inhibitors in the inhibition of thyroid cancer cells support this idea (92,93). In fact, the presence of genetic alterations in the two pathways seemed to predict an even better synergism in simultaneously targeting the two pathways to treat thyroid cancer (93).

Concluding Remarks

Genetic alterations are common in the PI3K/Akt pathway, which is the basis for aberrant signaling of this pathway in thyroid cancer. The recent identification of many activating genetic alterations, including mutations and genomic amplification/copy gain, in many key genes in this pathway represents a remarkable progress in our understanding of the oncogenic role of this pathway in thyroid tumorigenesis. Knowledge of the genotype of the PI3K/Akt pathway as well as that of the MAPK pathway will, and in fact, have already started to have an important impact on the development of novel diagnostic, prognostic, and therapeutic strategies for patients with thyroid cancer.

Footnotes

Portions of this review were presented at the Spring 2010 Meeting of the American Thyroid Association, “Thyroid Disorders in the Era of Personalized Medicine,” Minneapolis, MN, May 13–16, 2010.

Acknowledgment

This work was supported by NIH RO-1 grant R01CA134225 to the author.

Disclosure Statement

The author declares that no competing financial interests exist.

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