The oncogene BRAF V600E 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.
The oncogene BRAF(V600E) 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 ((131)I) total body scans, predicting a poorer outcome as treatment with (131)I is not effective. This last observation led us to investigate the role of BRAF(V600E) 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 BRAF(V600E) 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 BRAF(V600E) 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 (131)I uptake.
Riesco-Eizaguirre
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G
Instituto de Investigaciones Biomédicas Alberto Sols Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.
Gutiérrez-Martínez
P
P
García-Cabezas
M A
MA
Nistal
M
M
Santisteban
P
P
D000230:Adenocarcinoma / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018265:Carcinoma, Papillary, Follicular / Q000235:genetics; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D021381:Protein Transport; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000493:pharmacokinetics; D015996:Survival Rate; D027981:Symporters / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics*; D000099209:Sodium-Iodide Symporters
D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048493:Proto-Oncogene Proteins B-raf; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C482119:BRAF protein, human; C482125:MAP2K1 protein, human