RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

2013 ◽  
Vol 168 (6) ◽  
pp. 795-804 ◽  
Author(s):  
Ana Luísa Silva ◽  
Francisca Carmo ◽  
Maria João Bugalho
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Clinical Outcome ◽  
Thyroid Carcinoma ◽  
Small Gtpase ◽  
Papillary Thyroid ◽  
Poor Clinical Outcome ◽  
Thyroid Cells ◽  
Normal Thyroid ◽  
Histopathological Features ◽  
Mutational Status

ContextTheBRAFV600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). In colorectal cancer,BRAFV600E 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.ObjectiveWe aimed to analyze the expression of RAC1b in PTC and correlate its expression withBRAFV600E mutational status, histopathological features, and clinical outcome.Patients and methodsSixty-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.RAC1bexpression levels were determined by quantitative RT-PCR and western blotting.ResultsRAC1bwas expressed in thyroid and overexpressed in 46% of PTCs. Neither RAC1b overexpression nor V600E mutation correlated with histopathological features classically associated with worse prognosis.RAC1boverexpression was significantly associated with both V600E mutation (P=0.0008) and poor clinical outcome (P=0.0029). WhereasBRAFV600E alone did not associate with patient outcome (P=0.2865), the association ofRAC1boverexpression withBRAFV600E was overrepresented in the group with poorer clinical outcome (P=0.0044).ConclusionsPresent 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 betweenBRAFV600E and RAC1b contributing to poor clinical outcome. Future studies are needed to clarify the oncogenic potential of RAC1b in thyroid carcinogenesis.

scholarly journals Weightlessness Induced Apoptosis in Normal Thyroid Cells and Papillary Thyroid Carcinoma Cells via Extrinsic and Intrinsic Pathways

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 4172-4179 ◽  
Author(s):  
Peter Kossmehl ◽  
Mehdi Shakibaei ◽  
Augusto Cogoli ◽  
Manfred Infanger ◽  
Francesco Curcio ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Carcinoma Cells ◽  
Papillary Thyroid ◽  
Thyroid Cells ◽  
Normal Thyroid ◽  
Induced Apoptosis

scholarly journals The oncogene BRAFV600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I− targeting to the membrane

2006 ◽  
Vol 13 (1) ◽  
pp. 257-269 ◽  
Author(s):  
G Riesco-Eizaguirre ◽  
P Gutiérrez-Martínez ◽  
M A García-Cabezas ◽  
M Nistal ◽  
P Santisteban
Keyword(s):  
High Risk ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Prognostic Impact ◽  
Erk Pathway ◽  
Papillary Thyroid ◽  
Thyroid Cells ◽  
Genetic Event ◽  
Total Body

The oncogene BRAFV600E is the most frequent genetic event in papillary thyroid carcinoma (PTC) but its prognostic impact still remains to be elucidated. We evaluated a representative series of 67 individuals with PTC who underwent total thyroidectomy. BRAF-positive tumours correlated with early recurrences (32% vs 7.6%; P=0.02) during a median postoperative follow-up period of 3 years. Interestingly, within the recurrences, a significant majority had negative radioiodine (131I) total body scans, predicting a poorer outcome as treatment with 131I is not effective. This last observation led us to investigate the role of BRAFV600E and the MEK-ERK pathway in thyroid dedifferentiation, particularly in Na+/I− symporter (NIS) impairment, as this thyroid-specific plasma membrane glycoprotein mediates active transport of I− into the thyroid follicular cells. A subset of 60 PTC samples was evaluated for NIS immunoreactivity and, accordingly, we confirmed a significant low NIS expression and impaired targeting to membranes in BRAF-positive samples (3.5% vs 30%; P=0.005). Furthermore, experiments with differentiated PCCl3 thyroid cells demonstrated that transient expression of BRAFV600E sharply impaired both NIS expression and targeting to membrane and, surprisingly, this impairment was not totally dependent on the MEK-ERK pathway. We have concluded that BRAFV600E is a new prognostic factor in PTC that correlates with a high risk of recurrences and less differentiated tumours due to the loss of NIS-mediated 131I uptake.

Expression of the RET proto-oncogene in papillary thyroid carcinoma and its correlation with clinical outcome

2001 ◽  
Vol 88 (4) ◽  
pp. 557-563 ◽  
Author(s):  
P. Kjellman ◽  
D. L. Learoyd ◽  
M. Messina ◽  
G. Weber ◽  
A. Höög ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Clinical Outcome ◽  
Thyroid Carcinoma ◽  
Papillary Thyroid

scholarly journals TERT promoter mutations are associated with distant metastases in papillary thyroid carcinoma

2015 ◽  
Vol 172 (4) ◽  
pp. 403-413 ◽  
Author(s):  
Greta Gandolfi ◽  
Moira Ragazzi ◽  
Andrea Frasoldati ◽  
Simonetta Piana ◽  
Alessia Ciarrocchi ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Direct Sequencing ◽  
Distant Metastases ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Mutational Status ◽  
Metastatic Behavior ◽  
Well Differentiated ◽  
Promoter Mutations

ObjectiveTranscriptional activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene were reported at high frequency in aggressive poorly differentiated and anaplastic thyroid cancers. By contrast, the relevance of these mutations in the metastatic behavior of well-differentiated thyroid cancer is still to be defined. The aim of this work was to investigate the frequency ofTERTpromoter mutations in a remarkable cohort of well-differentiated papillary thyroid carcinoma that developed distant metastases (DM-PTCs) and to establish whether these mutations may be predictive of metastatic behavior.DesignWe analyzed the frequency ofTERTpromoter mutations in a group of 43 highly aggressive DM-PTCs. As controls, we analyzed these mutations in a group of 78 PTCs without distant metastases (control-PTCs). The possible correlation betweenTERTpromoter mutations and BRAF V600E mutation was also investigated.MethodsTERTpromoter mutational status was evaluated by direct sequencing of the hotspot harboring the C228T and the C250T mutations.ResultsIn the overall cohort of 121 PTCs analyzed, 17% of cases (21/121) carried a mutation in theTERTpromoter. Noticeably, 33% of DM-PTCs were mutated in theTERTpromoter while only 9% of the control-PTCs showed a mutation in this locus. We also observed a positive association between BRAF V600E andTERTC228T mutations in the cohort of DM-PTCs.ConclusionsThese results indicate thatTERTpromoter mutations are associated with the development of distant metastases in PTCs and may help in predicting aggressive behavior in this type of tumor.

scholarly journals TERT Promoter Mutations and Their Impact on Gene Expression Profile in Papillary Thyroid Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1597 ◽  
Author(s):  
Dagmara Rusinek ◽  
Aleksandra Pfeifer ◽  
Marta Cieslicka ◽  
Malgorzata Kowalska ◽  
Agnieszka Pawlaczek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Distant Metastases ◽  
Gene Set Enrichment Analysis ◽  
Braf V600e ◽  
Papillary Thyroid ◽  
Mutational Status

Background: Telomerase reverse transcriptase promoter (TERTp) mutations are related to a worse prognosis in various malignancies, including papillary thyroid carcinoma (PTC). Since mechanisms responsible for the poorer outcome of TERTp(+) patients are still unknown, searching for molecular consequences of TERTp mutations in PTC was the aim of our study. Methods: The studied cohort consisted of 54 PTCs, among them 24 cases with distant metastases. BRAF V600E, RAS, and TERTp mutational status was evaluated in all cases. Differences in gene expression profile between TERTp(+) and TERTp(−) PTCs were examined using microarrays. The evaluation of signaling pathways and gene ontology was based on the Gene Set Enrichment Analysis. Results: Fifty-nine percent (32/54) of analyzed PTCs were positive for at least one mutation: 27 were BRAF(+), among them eight were TERTp(+), and 1 NRAS(+), whereas five other samples harbored RAS mutations. Expression of four genes significantly differed in BRAF(+)TERTp(+) and BRAF(+)TERTp(−) PTCs. Deregulation of pathways involved in key cell processes was observed. Conclusions: TERTp mutations are related to higher PTC aggressiveness. CRABP2 gene was validated as associated with TERTp mutations. However, its potential use in diagnostics or risk stratification in PTC patients needs further studies.

scholarly journals Pre-sternal thyroid swellings: a case of rare aberrant site recurrence and review of literature

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Lovenish Bains ◽  
Sushant Bhatia ◽  
Rohit Kaushik ◽  
Sudhir Kumar Jain ◽  
Chandra Bhushan Singh ◽  
...  
Keyword(s):  
Lymph Node ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
De Novo ◽  
Anterior Part ◽  
Thyroid Tissue ◽  
Papillary Thyroid ◽  
Thyroid Cells ◽  
Thyroid Swelling ◽  
The Right

Abstract Background Thyroid swellings enlarge caudally into the mediastinum behind the sternum. Pre-sternal swelling of thyroid origin is very rare. We present our case of pre-sternal thyroid swelling which was albeit a surprisingly rare site of papillary thyroid carcinoma recurrence and review of pre-sternal thyroid swellings reported till date. Case summary A 60 year old female presented with a painless, progressive swelling on the anterior part of the chest for the past 2 years. A 15 cm × 8 cm vertically aligned, non tender, well defined swelling was present on the pre-sternal region, with consistency ranging from soft to firm. The swelling was fixed to the underlying tissues and a fixed level IV lymph node was palpable on the right side. Ultrasonography revealed a large mass of 15 × 7 cm with multiple cystic areas. Fine needle aspiration cytology was inconclusive twice. Patient had undergone a total thyroidectomy for papillary carcinoma 10 years back. Computed tomography findings revealed a large 15 × 6.6 × 7 cm lobulated, pre-sternal, soft tissue lesion with solid & cystic components. The mass was infiltrating the right sided strap muscles and sternocleidomastoid. FNAC was inconclusive and thyroid scan could not pick up any activity in the mass. Henceforth a PET scan was done that showed increased FDG uptake by the lesion and the level IV lymph node. The patient underwent wide excision of the mass with right functional neck dissection, along with removal with both sternal head of sternocleido-mastoid, the strap muscles and the surrounding fascia. Histopathology confirmed papillary thyroid carcinoma. Patient received post-operative radioactive iodine ablation and is healthy with no recurrence up to 30 months of follow up. Discussion The mechanisms for pre-sternal thyroid swelling are not understood due to paucity of cases. The mechanisms proposed are invasion of strap muscles and cervical linea alba and tumor cells spread anterior to sternum, truly ectopic thyroid tissue, de novo carcinogenesis in the embryonal remnants like the thyro-thymic residues, sequestered thyroid tissue which grows later or migration of thyroid cells, incomplete clearance at the time of primary surgery or intraoperative seeding. Conclusion Pre-sternal region masses of thyroid origin are very rare. A proper work up, suspicion for thyroid mass and array of tests will be required to come to a provisional diagnosis. Since the masses reported in literature were primarily malignant, any such mass may be treated on lines of malignancy with radical surgery.

scholarly journals Long-term outcomes of follicular variant vs classic papillary thyroid carcinoma

2018 ◽  
Vol 7 (12) ◽  
pp. 1226-1235 ◽  
Author(s):  
Lauren E Henke ◽  
John D Pfeifer ◽  
Thomas J Baranski ◽  
Todd DeWees ◽  
Perry W Grigsby
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Primary Study ◽  
Papillary Thyroid ◽  
Long Term Outcomes ◽  
Follicular Variant ◽  
Kaplan Meier ◽  
Mutational Status ◽  
Clinicopathologic Factors

The majority of papillary thyroid carcinoma (PTC) cases comprise classic papillary (C-PTC) and follicular variant (FV-PTC) histologic sub-types. Historically, clinical equivalency was assumed, but recent data suggest C-PTC may have poorer outcomes. However, large single-institution series with long-term outcomes of C-PTC and FV-PTC, using modern pathologic criteria for FV-PTC, are needed. Our objective was to compare prevalence and impact of clinicopathologic factors, including BRAF mutation status, on long-term outcomes of C-PTC and FV-PTC. We hypothesized that patients with C-PTC would have higher risk disease features and worse survival outcomes. This retrospective study included 1293 patients treated at a single, US academic institution between 1943 and 2009 with mean follow-up of 8.6 years. All patients underwent either partial or total thyroidectomy and had invasive C-PTC or FV-PTC per modern pathology criteria. Primary study measurements included differences in recurrence-free survival (RFS), disease-specific survival (DSS) and associations with clinicopathologic factors including the BRAF mutation. Compared to FV-PTC, C-PTC was associated with multiple features of high-risk disease (P < 0.05) and significantly reduced RFS and DSS. Survival differences were consistent across univariate, multivariate and Kaplan–Meier analyses. BRAF mutations were more common in C-PTC (P = 0.002). However, on Kaplan–Meier analysis, mutational status did not significantly impact RFS or DSS for patients with either histologic sub-type. C-PTC therefore indicates higher-risk disease and predicts for significantly poorer long-term outcomes when compared to FV-PTC. The nature of this difference in outcome is not explained by traditional histopathologic findings or by the BRAF mutation.

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