Mutational Profile of Advanced Primary and Metastatic Radioactive Iodine-Refractory Thyroid Cancers Reveals Distinct Pathogenetic Roles for BRAF, PIK3CA, and AKT1

Human Oncology and Pathogenesis Program and Departments of Medicine and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Cancer Research (Impact Factor: 9.33). 07/2009; 69(11):4885-93. DOI: 10.1158/0008-5472.CAN-09-0727
Source: PubMed


Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors.

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Available from: Adriana Heguy, Aug 13, 2014
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    • "Moreover, mutations in the telomerase gene (TERT) are frequently seen in aggressive thyroid cancers, including in poorly differentiated and anaplastic thyroid cancers [7] [8], and lead to increased transcriptional activity of TERT. However, additional mutations in MAPK signaling (RAS and BRAF genes), in PI3K signaling (PIKCA and PTEN), and in Wnt signaling (í µí»½-catenin and APC) have also been detected in ATC [9] [10] [11] [12]. "
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    ABSTRACT: Anaplastic thyroid cancer (ATC) is among the most lethal types of cancers, characterized as a fast-growing and highly invasive thyroid tumor that is unresponsive to surgery and radioiodine, blunting therapeutic efficacy. Classically, genetic alterations in tumor suppressor TP53 are frequent, and cumulative alterations in different signaling pathways, such as MAPK and PI3K, are detected in ATC. Recently, deregulation in microRNAs (miRNAs), a class of small endogenous RNAs that regulate protein expression, has been implicated in tumorigenesis and cancer progression. Deregulation of miRNA expression is detected in thyroid cancer. Upregulation of miRNAs, such as miR-146b, miR-221, and miR-222, is observed in ATC and also in differentiated thyroid cancer (papillary and follicular), indicating that these miRNAs' overexpression is essential in maintaining tumorigenesis. However, specific miRNAs are downregulated in ATC, such as those of the miR-200 and miR-30 families, which are important negative regulators of cell migration, invasion, and epithelial-to-mesenchymal transition (EMT), processes that are overactivated in ATC. Therefore, molecular interference to restore the expression of tumor suppressor miRNAs, or to blunt overexpressed oncogenic miRNAs, is a promising therapeutic approach to ameliorate the treatment of ATC. In this review, we will explore the importance of miRNA deregulation for ATC cell biology.
    Full-text · Article · Aug 2014 · International Journal of Endocrinology
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    • "A specific therapy for oncogenic Ras mutations in thyroid cancer is still lacking. It was found that, in animal models, combined treatment with MEK and PI3K/AKT/mTOR pathway inhibitors was more efficient than monotherapy [33]. In the clinical studies performed, farnesyl transferase inhibitors targeted mutant RAS, which could, in future, be considered as a therapeutic for the treatment of poor and undifferentiated TCs [31]. "
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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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    • "Outcomes could be improved with routine assessment of pro-metastatic biomarkers, which could enable earlier metastatic potential of this type of fatal thyroid cancer. The BRAFV600E mutation is the most prevalent genetic alteration (greater than 50%) in papillary thyroid cancer (PTC) and is implicated in the progression of PTC to ATC (4–6), a crucial challenge in thyroid cancer. Our previous studies demonstrated the pro-metastatic role of the secreted extracellular matrix (ECM) protein thrombospondin-1 (TSP-1) in BRAFV600E-positive PTC (5, 7, 8) and indicated that TSP-1 increased phosphorylation of ERK1/2 (5). "
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    ABSTRACT: Background and Rationale: Anaplastic thyroid cancer (ATC) is characterized by pleomorphic cells, has a poor prognosis, is highly devastating disease, and is not curable. No reliable biomarkers of metastatic potential, helpful for early diagnosis of ATC and therapeutic response have been found yet. Thrombospondin-1 (TSP-1) plays a fundamental role in cancer progression by regulating cell stromal cross-talk in the tumor microenvironment. Goals: Our goal was to understand whether TSP-1 could affect protein levels of its integrin receptors (e.g., ITGα3, α6, and β1) and cell morphology in BRAFV600E-ATC cells in vitro and in vivo. Experimental Design: Anaplastic thyroid cancer-derived cell cultures and western blotting were used to assess integrin protein expression upon TSP-1 silencing. Immunohistochemistry was performed on orthotopic primary human ATC and metastatic ATC in lung tissue to compare TSP-1 and integrin protein expression levels. Results: TSP-1 knock-down down-regulates ITGα3, α6, and β1 in BRAFV600E-human ATC cells. BRAFV600E-ATC cells with TSP-1 knock-down were rounded compared to control cells, which displayed a spread morphology. TSP-1 knock-down also reduced TSP-1, ITGα3, α6, and β1 protein expression levels in vivo in the ATC microenvironment, which is enriched in stromal and inflammatory cells. Conclusion: TSP-1 silencing causes changes in ITG levels and ATC cell morphology. The assessment of TSP-1 and ITG levels might contribute to earlier metastatic potential of BRAFV600E-positive aggressive thyroid cancers, and allow improved patient selection for clinical trials.
    Full-text · Article · Dec 2013 · Frontiers in Endocrinology
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