Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers.
Activating mutations in the BRAF kinase gene have recently been reported in human cancers. The aim of the present study was to determine the frequency of BRAF mutations in thyroid cancer and their correlation with clinicopathological parameters. We analyzed exons 11 and 15 of BRAF gene in six human thyroid cancer cell lines and 207 paraffin-embedded thyroid tumor tissues. A missense mutation was found at T1796A (V599E) in exon 15 in four of the six cell lines and 51 of 207 thyroid tumors (24.6%; 0 of 20 follicular adenoma, 0 of 11 follicular carcinoma, 49 of 170 papillary carcinomas, and 2 of 6 undifferentiated carcinomas). Activation of MAPK kinase-MAPK pathway was observed in cell lines harboring BRAF mutation. BRAF mutation-associated enhanced cell growth was suppressed by MAPK kinase inhibitor, U0126. Examination of 126 patients with papillary thyroid cancer showed that BRAF mutation correlated significantly with distant metastasis (P = 0.033) and clinical stage (P = 0.049). Our results indicate that activating mutation of BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers.
Namba
Hiroyuki
H
Department of Molecular Medicine, Tissue and Histopathology Section, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Sakamoto, Japan. namba@net.nagasaki-u.ac.jp
Nakashima
Masahiro
M
Hayashi
Tomayoshi
T
Hayashida
Naomi
N
Maeda
Shigeto
S
Rogounovitch
Tatiana I
TI
Ohtsuru
Akira
A
Saenko
Vladimir A
VA
Kanematsu
Takashi
T
Yamashita
Shunichi
S
D000328:Adult; D002291:Carcinoma, Papillary / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics*; D016612:Paraffin Embedding; D048493:Proto-Oncogene Proteins B-raf; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
D004273:DNA, Neoplasm; D015513:Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases