Molecular Analysis of Thyroid Tumors

Bhaijee, Feriyl; Nikiforov, Yuri E.

doi:10.1007/s12022-011-9170-y

Cited by 94 publications

(84 citation statements)

References 93 publications

(118 reference statements)

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“…Activating mutations of several genes in the RET-RAS-BRAF-MEK-ERK pathway (MAP kinase pathway -MAPK) have been identified in the majority of PTCs (7,8,9). BRAF and RAS point mutations as well as RET/PTC rearrangements are identified in more than 70% of PTCs (7).…”

Section: Introductionmentioning

confidence: 99%

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RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

Silva¹,

Carmo²,

Bugalho

2013

European Journal of Endocrinology

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Context: The BRAF V600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). In colorectal cancer, BRAF V600E was described to functionally cooperate with RAC1b, a hyperactive splice variant of the small GTPase RAC1, to sustain cell survival. This interplay has never been investigated in PTCs.Objective: We aimed to analyze the expression of RAC1b in PTC and correlate its expression with BRAF V600E mutational status, histopathological features, and clinical outcome. Patients and methods: Sixty-one patients and 87 samples (61 PTCs and 26 normal thyroid tissues) were included. Patients were divided into two groups based on longitudinal evolution and final outcome. RAC1b expression levels were determined by quantitative RT-PCR and western blotting. Results: RAC1b was expressed in thyroid and overexpressed in 46% of PTCs. Neither RAC1b overexpression nor V600E mutation correlated with histopathological features classically associated with worse prognosis. RAC1b overexpression was significantly associated with both V600E mutation (PZ0.0008) and poor clinical outcome (PZ0.0029). Whereas BRAF V600E alone did not associate with patient outcome (PZ0.2865), the association of RAC1b overexpression with BRAF V600E was overrepresented in the group with poorer clinical outcome (PZ0.0044). Conclusions: Present results document, for the first time, expression of RAC1b in normal thyroid cells as well as overexpression in a subset of PTCs. Furthermore, they suggest a possible interplay between BRAF V600E and RAC1b contributing to poor clinical outcome. Future studies are needed to clarify the oncogenic potential of RAC1b in thyroid carcinogenesis.

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Section: Introductionmentioning

confidence: 99%

“…BRAF and RAS point mutations as well as RET/PTC rearrangements are identified in more than 70% of PTCs (7). Most often, these alterations are mutually exclusive (7,8,9,10). BRAF V600E mutation is the most frequent genetic alteration in PTCs, occurring in 29-83% of cases (8,9,11).…”

Section: Introductionmentioning

confidence: 99%

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

Silva¹,

Carmo²,

Bugalho

2013

European Journal of Endocrinology

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“…H-, N-, and K-RAS-activating point mutations in specific hot spots at codons 12, 13, and 61 are also present in PTC cells, particularly in the follicular variant of PTC (Bhaijee & Nikiforov 2011). These mutations cause the loss of GTPase activity so that the kinase becomes constitutively activated.…”

Section: :4mentioning

confidence: 99%

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

Viola

Valerio

Molinaro

et al. 2016

Endocrine-Related Cancer

164

130

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Thyroid cancer is rare, but it is the most frequent endocrine malignancy. Its prognosis is generally favorable, especially in cases of well-differentiated thyroid cancers (DTCs), such as papillary and follicular cancers, which have survival rates of approximately 95% at 40 years. However, 15-20% of cases became radioiodine refractory (RAI-R), and until now, no other treatments have been effective. The same problems are found in cases of poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers and in at least 30% of medullary thyroid cancer (MTC) cases, which are very aggressive and not sensitive to radioiodine. Tyrosine kinase inhibitors (TKIs) represent a new approach to the treatment of advanced cases of RAI-R DTC, MTC, PDTC, and, possibly, ATC. In the past 10 years, several TKIs have been tested for the treatment of advanced, progressive, and RAI-R thyroid tumors, and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC and vandetanib and cabozantinib for MTC. The objective of this review is to present the current status of the treatment of advanced thyroid cancer with the use of innovative targeted therapies by describing both the benefits and the limits of their use based on the experiences reported so far. A comprehensive analysis and description of the molecular basis of these therapies, as well as new therapeutic perspectives, are reported. Some practical suggestions are given for both the choice of patients to be treated and their management, with particular regard to the potential side effects.

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“…These rates represent a sixfold increase since 1975 (1). A combination of more sensitive detection methods and unknown molecular/environmental factors likely contribute to this higher incidence of thyroid cancer (2). Among the three major groups of thyroid cancer-papillary (PTC), follicular (FTC), and undifferentiated (UTC)-PTC is the most common form, accounting for 80% of all thyroid carcinoma, followed by FTC and UTC at approximately 15% and 2% respectively (2).…”

Section: Introductionmentioning

confidence: 99%

“…A combination of more sensitive detection methods and unknown molecular/environmental factors likely contribute to this higher incidence of thyroid cancer (2). Among the three major groups of thyroid cancer-papillary (PTC), follicular (FTC), and undifferentiated (UTC)-PTC is the most common form, accounting for 80% of all thyroid carcinoma, followed by FTC and UTC at approximately 15% and 2% respectively (2). In 3-7% of cases, PTC and FTC occur as part of a hereditary syndrome (3,4), which involves mutations in the PTEN gene locus (10q22-23) and inactivating mutations in the gene encoding the regulatory subunit 1A of the cAMP-dependent protein kinase (PKAR1A; 2p16, 17q23) resulting in the constitutive activation of protein kinase A (5,6), which has been linked to nonthyroidal tumors in disease states such as Cowden's disease (5).…”

Section: Introductionmentioning

confidence: 99%

Three-Dimensional Telomere Dynamics in Follicular Thyroid Cancer

Wark

Danescu

Natarajan

et al. 2014

Thyroid

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Background: Over the last decade, annual incidence rates for thyroid cancer have been among the highest of all cancers in the Western world. However, the genomic mechanisms impacting thyroid carcinogenesis remain elusive. Methods: We employed an established mouse model of follicular thyroid cancer (FTC) with a homozygous proline to valine mutation (Thrb PV/PV ) in the thyroid receptor b1 (TRb1) and applied quantitative threedimensional (3D) telomere analysis to determine 3D telomeric profiles in Thrb PV/PV , Thrb PV/ + , and Thrbmouse thyrocytes before and after histological presentation of FTC.Results: Using quantitative fluorescent in situ hybridization (Q-FISH) and TeloViewÔ image analysis, we found altered telomeric signatures specifically in mutant mouse thyrocytes. As early as 1 month of age, Thrb PV/PV mouse thyrocytes showed more telomeres than normal and heterozygous age-matched counterparts. Importantly, at the very early age of 1 month, 3D telomeric profiles of Thrb PV/PV thyrocyte nuclei reveal genetic heterogeneity with several nuclei populations exhibiting different telomere numbers, suggestive of various degrees of aneuploidy within the same animal. This was detected exclusively in Thrb PV/PV mice well before the presentation of histological signs of thyroid carcinoma. Conclusions: We identified quantitative 3D telomere analysis as a novel tool for early detection and monitoring of thyrocyte chromosomal (in)stability. This technique has the potential to identify human patients at risk for developing thyroid carcinoma.

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Molecular Analysis of Thyroid Tumors

Cited by 94 publications

References 93 publications

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

Three-Dimensional Telomere Dynamics in Follicular Thyroid Cancer

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