BRAFV600E mutation, but not RET/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer.
A low sodium iodide symporter (NIS) expression has been shown in papillary thyroid carcinomas (PTCs) harboring the BRAFV600E mutation. In the present study, we analyzed the mRNA expression of thyroid differentiation genes, glucose transporter (GLUT)-1 and GLUT-3, in 78 PTCs according to the presence of BRAFV600E or RET/PTC rearrangements. We found BRAFV600E and RET/PTC rearrangements in 35.8 and 19.4% of PTCs respectively. The mRNA expression of NIS and thyroperoxidase (TPO) genes were significantly lower (P<0.0001 and P=0.004 respectively) in BRAFV600E-positive PTC with respect to non-mutated samples. In support of this result, immunohistochemistry showed that the percentage of NIS-positive cells was significantly lower (P=0.005) in BRAFV600E-mutated PTC (mean 53.5%) than in negative cases (mean 72.6%). In contrast, no difference either in NIS or in any other thyroid differentiation genes' mRNA expression was found in PTC with or without RET/PTC rearrangements. When GLUT-1 and GLUT-3 mRNA expression was considered, no correlation was found either in BRAFV600E- nor in RET/PTC-mutated cases. In conclusion, this study confirmed the presence of a genetic alteration of BRAF and/or RET oncogenes in 64% of PTC cases and revealed a significant correlation of BRAFV600E mutation with a lower expression of both NIS and TPO. This latter finding could indicate that an early dedifferentiation process is present at the molecular level in BRAFV600E-mutated PTC, thus suggesting that the previously demonstrated poor prognostic significance of BRAFV600E mutation could be related to the dedifferentiation process more than to a more advanced stage at diagnosis.
Departments of Endocrinology and Metabolism Oncology Surgery, University of Pisa, 56100 Pisa, Italy.
Cristina
C
Romei
Raffaele
R
Ciampi
Pinuccia
P
Faviana
Laura
L
Agate
Eleonora
E
Molinaro
Valeria
V
Bottici
Fulvio
F
Basolo
Paolo
P
Miccoli
Furio
F
Pacini
Aldo
A
Pinchera
Rossella
R
Elisei
D000328:Adult; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D051272:Glucose Transporter Type 1 / Q000235:genetics; D051274:Glucose Transporter Type 3 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013972:Thyrotropin / Q000097:blood; D000099209:Sodium-Iodide Symporters
D001324:Autoantigens; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D007453:Iodide Peroxidase; D033862:Iron-Binding Proteins; D048493:Proto-Oncogene Proteins B-raf; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger; D027981:Symporters; D013972:Thyrotropin; D000099209:Sodium-Iodide Symporters; C495677:SLC2A1 protein, human; C495687:SLC2A3 protein, human; C056658:TPO protein, human; C099282:RET protein, human; C482119:BRAF protein, human