BRAF V600E and decreased NIS and TPO expression are associated with aggressiveness of a subgroup of papillary thyroid microcarcinoma.
BACKGROUND
Thyroid cancer incidence has dramatically increased worldwide over the last two decades. The rise is mostly due to an increased detection of small papillary thyroid carcinomas (PTCs) (≤20  mm), predominantly microPTC (≤10  mm). Although small tumors generally have an excellent outcome, a considerable percentage may have a more aggressive disease and worse prognosis. The clinical challenge is to preoperatively identify those tumors that are more likely to recur.


OBJECTIVE
To improve risk stratification and patient management, we sought to determine the prognostic value of BRAF V600E, NRAS or RET/PTC mutations in patients with PTC measuring <20  mm, mainly microPTC.


METHODS
The prevalence of RET/PTC fusion genes was examined by quantitative RT-PCR. BRAF V600E and NRAS Q61 mutations were determined by PCR sequencing. To further elucidate why some small PTC are less responsive to radioactive iodine treatment therapy, we explored if these genetic alterations may modulate the expression of iodine metabolism genes (NIS, TPO, TG, TSHR and PDS) and correlated with clinico-pathological findings that are predictors of recurrence.


RESULTS
This study shows that tumors measuring ≤20  mm exhibited higher prevalence of BRAF V600E mutation, which correlated with aggressive histopathological parameters, higher risk of recurrence, and lower expression of NIS and TPO. Although this correlation was not found when microPTC were evaluated, we show that tumors measuring 7-10  mm, which were positive for BRAF mutation, presented more aggressive features and lower expression of NIS and TPO.


CONCLUSIONS
We believe that our findings will help to decide the realistic usefulness of BRAF V600E mutation as a preoperative marker of poor prognosis in small PTC, primarily in microPTC.
Laboratório as Bases Genéticas dos Tumores da Tiroide Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669 - 11° andar, 04039-032 São Paulo, São Paulo, Brazil Disciplina de Cirurgia de Cabeça e Pescoço Departamento de Cirurgia, Universidade de São Paulo, São Paulo, São Paulo, Brazil.
André Uchimura
AU
Bastos
Laboratório as Bases Genéticas dos Tumores da Tiroide Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669 - 11° andar, 04039-032 São Paulo, São Paulo, Brazil Disciplina de Cirurgia de Cabeça e Pescoço Departamento de Cirurgia, Universidade de São Paulo, São Paulo, São Paulo, Brazil.
Gisele
G
Oler
Laboratório as Bases Genéticas dos Tumores da Tiroide Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669 - 11° andar, 04039-032 São Paulo, São Paulo, Brazil Disciplina de Cirurgia de Cabeça e Pescoço Departamento de Cirurgia, Universidade de São Paulo, São Paulo, São Paulo, Brazil.
Bruno Heidi Nakano
BH
Nozima
Laboratório as Bases Genéticas dos Tumores da Tiroide Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669 - 11° andar, 04039-032 São Paulo, São Paulo, Brazil Disciplina de Cirurgia de Cabeça e Pescoço Departamento de Cirurgia, Universidade de São Paulo, São Paulo, São Paulo, Brazil.
Raquel Ajub
RA
Moysés
Laboratório as Bases Genéticas dos Tumores da Tiroide Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669 - 11° andar, 04039-032 São Paulo, São Paulo, Brazil Disciplina de Cirurgia de Cabeça e Pescoço Departamento de Cirurgia, Universidade de São Paulo, São Paulo, São Paulo, Brazil j.cerutti@unifesp.br.
Janete Maria
JM
Cerutti
D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000235:genetics; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics; D007455:Iodine / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011989:Receptors, Thyrotropin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000076988:Sulfate Transporters; D027981:Symporters / Q000235:genetics; D013954:Thyroglobulin / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D047368:Tumor Burden; D055815:Young Adult; D000099209:Sodium-Iodide Symporters
D001324:Autoantigens; D020558:GTP Phosphohydrolases; D007453:Iodide Peroxidase; D007455:Iodine; D033862:Iron-Binding Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; D048493:Proto-Oncogene Proteins B-raf; D011989:Receptors, Thyrotropin; D000076988:Sulfate Transporters; D027981:Symporters; D013954:Thyroglobulin; D000099209:Sodium-Iodide Symporters; C085609:SLC26A4 protein, human; C056658:TPO protein, human; C093573:ret-PTC fusion oncoproteins, human; C482119:BRAF protein, human; C579846:NRAS protein, human