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Functional characterization of the novel BRAF complex mutation, BRAF V600delinsYM , identified in papillary thyroid carcinoma
Author(s) -
Matsuse Michiko,
Mitsutake Norisato,
Tanimura Susumu,
Ogi Tomoo,
Nishihara Eijun,
Hirokawa Mitsuyoshi,
Fuziwara Cesar S.,
Saenko Vladimir A.,
Suzuki Keiji,
Miyauchi Akira,
Yamashita Shunichi
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27709
Subject(s) - mutation , cancer research , transversion , mutant , biology , microbiology and biotechnology , v600e , sorafenib , exon , point mutation , kinase , thyroid carcinoma , gene , genetics , thyroid , hepatocellular carcinoma
An activating mutation in the BRAF gene is the most common genetic alteration in papillary thyroid carcinomas (PTCs). The mutation in PTCs is almost a c.1799T>A transversion, resulting in a p.V600E amino acid substitution (BRAF V600E ). Here, we report a novel complex BRAF mutation identified in 4/492 Japanese PTC cases (0.81%). The mutation was comprised of one nucleotide substitution at position 1798, followed by an in‐frame insertion of three nucleotides, c.1798delinsTACA in Exon 15, resulting in p.V600delinsYM. In silico three‐dimensional protein structure prediction implied altered kinase activity of this mutant. In vitro kinase assay and western blotting revealed that this mutation conferred high kinase activity on the BRAF protein, leading to constitutive activation of the MAPK signaling pathway. The mutation also showed high transforming ability in focus formation assay using NIH3T3 cells. The degree of all the functional characteristics was comparable to that of BRAF V600E , and treatment with a BRAF inhibitor Sorafenib was also equally effective in this mutant. These findings suggest that the novel BRAF mutation, BRAF V600delinsYM , is a gain‐of‐function mutation and plays an important role in PTC development.