Genetic Alterations in the Phosphatidylinositol-3 Kinase/Akt Pathway in Thyroid Cancer

Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Thyroid: official journal of the American Thyroid Association (Impact Factor: 4.49). 07/2010; 20(7):697-706. DOI: 10.1089/thy.2010.1646
Source: PubMed


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.

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    • "Thyroid cancer is one of the earliest cases where activating RAS mutations were discovered[2]. Today, the role of RAS oncogene in thyroid tumorigenesis has been well established345. Mutations in RAS genes occur, on average, in 30–45 % follicular thyroid cancer (FTC), 30–45 % follicular variant papillary thyroid cancer (FVPTC), 20–40 % poorly differentiated thyroid cancer (PDTC), 10–20 % anaplastic thyroid cancer, and rarely classical papillary thyroid cancer (PTC). RAS mutations also occur in 20–25 % benign follicular thyroid adenoma (FTA). "
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    ABSTRACT: RAS mutations play an important role in thyroid tumorigenesis. Considerable effort has been made in the last decade to apply RAS mutations as molecular markers to the clinical management of thyroid nodules and thyroid cancer. Yet, for the low diagnostic sensitivities and specificities of RAS mutations, when used alone, and for their uncertain role in the clinical outcomes of thyroid cancer, it has been unclear how to appropriately use them to assist the management of thyroid nodules and thyroid cancer. Studies from recent years, now added from the Alexander group, have shed light on this issue, making a blurred clinical picture now emerge clearer—RAS mutations, when combined with other genetic markers, have high diagnostic negative predictive values for thyroid cancer; cytologically benign thyroid nodules, including those positive for RAS mutations, have long-term clinical stability when non-surgically managed; and differentiated thyroid cancers harboring RAS mutations alone have an excellent prognosis. This progress in understanding RAS mutations in thyroid cancer is showing a major impact on molecular-based practice in the management of thyroid cancer. Please see related research articles: and
    Full-text · Article · Dec 2016 · BMC Medicine
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    • "In addition to the above, the oncogene AKT1 is overexpressed and plays a key role in thyroid tumorigenesis [42, 43]. This activation occurs in approximately 5–10% of ATC cases (Table 1). "
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    ABSTRACT: Thyroid cancer is an endocrine malignancy with an incidence rate that has been increasing steadily over the past 30 years. While well-differentiated subtypes have a favorable prognosis when treated with surgical resection and radioiodine, undifferentiated subtypes, such as anaplastic thyroid cancer (ATC), are far more aggressive and have a poor prognosis. Conventional therapies (surgical resection, radiation, chemotherapy, and radioiodine) have been utilized for treatment of ATC, yet these treatments have not significantly improved the overall mortality rate. As cancer is a genetic disease, genetic alterations such as mutations, fusions, activation of oncogenes, and silencing of tumor suppressors contribute to its aggressiveness. With the use of next-generation sequencing and the Cancer Genome Atlas, mutation-directed therapy is recognized as the upcoming standard of care. In this review, we highlight the known genetic landscape of ATC and the need for a comprehensive genetic characterization of this disease in order to identify additional therapeutic targets to improve patient outcomes.
    Full-text · Article · Sep 2014 · Journal of Oncology
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    • "The important role that these genetic alterations play in TC is an important guide for the development of new gene-based diagnostic, prognostic and therapeutic strategies. Although the standard therapeutic strategy for the treatment of thyroid cancer still includes surgery, radioactive iodine (RAI) treatment and thyroid suppression therapy, an understanding of the specific factors that constitute the signalling pathways involved in TC has provided opportunities for targeted therapies [1, 14, 15]. As a result of the establishment of these targets of thyroid cancer, several targeted therapies, such as sorafenib, gefitinib, axitinib, motesanib, sunitinib, imatinib, and pazopanib, were generated. "
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    ABSTRACT: Aim of the study Important signalling pathways play fundamental roles in the pathogenesis of thyroid carcinoma (TC). PTEN, mTOR, PI3K-p85 and K-Ras are the principal factors involved in these signalling pathways. To immunohistochemically examine the expressions of PI3K, mTOR and PTEN in patients suffering from follicular TC, papillary TC or variants thereof, as well as to investigate KRAS mutations via PCR to determine their clinical and prognostic relevance to differentiated thyroid cancer. Material and methods The expression of PTEN, PI3K-p85 and mTOR was immunohistochemically examined, and the mutation of K-Ras was examined via PCR. The results obtained were compared to the clinico-pathologic characteristics of the patients. Results A significant correlation was found between p85 expression and lymphovascular invasions and between PTEN expression and multifocality (p = 0.048 and p = 0.04, respectively), and a correlation between p85 and capsular invasion was found, with a borderline statistical significance (p = 0.056). No expression of PTEN, p85 or Mtor was detected in normal tissue. K-Ras mutation was examined in 66 of the 101 patients (57.4%), and the percentage of patients exhibiting a K-Ras mutation was 17.4%. All of the patients exhibiting a K-Ras mutation were women (p = 0.047). The disease-free survival was 44.6 months (95% CI: 37.9–51.3) and was statistically significantly higher in the group that displayed level 1 or lower expression of p85 (p = 0.043). Conclusions The expression levels of the aforementioned markers were significantly higher in TC cells than in normal tissue. A significant correlation was detected between K-Ras mutation and gender. This study demonstrates that p85 and PTEN are markers that should be evaluated in further studies of TC.
    Full-text · Article · Jul 2014 · Contemporary Oncology / Wspólczesna Onkologia
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