BRAF mutation in thyroid cancer

Han

et al. 2015

Nucl Med Mol Imaging

Purpose The BRAF mutation, a potential prognostic factor in papillary thyroid carcinoma (PTC), is associated with a high expression of the glucose transporter gene. We investigated which clinicopathologic factors, including BRAF mutation status, influence 18 F-fluoro-2-deoxyglucose ( 18 F-FDG) avidity. Methods We retrospectively reviewed 55 patients who underwent BRAF analysis from biopsy-confirmed PTC and 18 F-FDG positron emission tomography/computed tomography within 6 months before undergoing thyroid surgery from September 2008 to August 2014. Tumors were considered to be 18 F-FDG avid if the uptake was greater than that of the liver. 18 F-FDG uptake of PTCs was also analyzed semiquantitatively using SUV max . The association between 18 F-FDG avidity and clinicopathologic variables (age, tumor size, perithyroidal extension, cervical lymph node status, and BRAF mutation status) was investigated. Results Twenty-nine (52.7 %) of 55 patients had 18 F-FDGavid PTCs. PTCs with the BRAF mutation showed higher 18 F-FDG avidity (24/38, 63.2 %) than those without (5/17, 29.4 %). The BRAF mutation (p=0.025) and tumor size (p= 0.003) were significantly associated with 18 F-FDG avidity in univariate analysis, and the BRAF mutation status remained significant after adjusting for tumor size in multivariate analysis (p=0.015). In the subgroup of tumor size≥1 cm, the BRAF mutation was the only factor significantly associated with 18 F-FDG avidity (p=0.021). The mean SUV max of PTCs with the BRAF mutation was significantly higher than that of those without (4.89±6.12 vs. 1.96±1.10, p=0.039). Conclusions The BRAF mutation must be one of the most important factors influencing 18 F-FDG avidity in PTCs, especially in those with a tumor size≥1 cm.

Section: Introductionmentioning

confidence: 99%

Association Between 18F-FDG Avidity and the BRAF Mutation in Papillary Thyroid Carcinoma

Han

et al. 2015

Nucl Med Mol Imaging

“…4 The mutation in PTCs is almost a thymine-to-adenine transversion at nucleotide 1799 (c.1799T>A) in Exon 15, resulting in a valine-to-glutamic acid substitution at amino acid 600 (p.V600E). However, several other mutations affecting the BRAF gene have been found in rare cases ( Table 1).…”

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confidence: 99%

Functional characterization of the novel BRAF complex mutation, BRAF^V600delinsYM, identified in papillary thyroid carcinoma

Matsuse

Mitsutake

Tanimura

et al. 2012

Intl Journal of Cancer

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 (BRAFV600E). 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 BRAFV600E, and treatment with a BRAF inhibitor Sorafenib was also equally effective in this mutant. These findings suggest that the novel BRAF mutation, BRAFV600delinsYM, is a gain‐of‐function mutation and plays an important role in PTC development.

“…18 BRAF represent one type of RAF serine/threonine kinases that play a central role in the transduction of signals along the RAS-RAF-MAPK pathway regulat-ing cell growth, differentiation, and apoptosis in response to cytokines, hormones, and growth factors. 19 This major genetic alteration involved in the pathogenesis of PTC is an activating mutation of the BRAF gene occurring in about 45% of the sporadic type (reviewed by Xing 20 ) resulting in increased kinase activity of BRAF with activation of ERK. BRAF-activating missense point mutations in the kinase domain are clustered in exons 11 and 15 of the gene.…”

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confidence: 99%

“…About 80% of all mutations display a thymine-to-adenine transversion at nucleotide 1799 (T1799A) leading to a substitution of valine by glutamic acid at amino-acid residue 600 (V600E) in exon 15. 21 BRAF mutation-positive tumours have been associated with various subtypes, 20 older age of patients, 22,23 extrathyroidal extension, 22,24,25 and more advanced tumour stage at presentation. 22,25,26 BRAF mutations have also been linked to tumour progression from well-differentiated papillary to anaplastic carcinoma, possibly with the intermediate step of poorly differentiated carcinoma.…”

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confidence: 99%

Diffuse sclerosing variant of papillary thyroid carcinoma: lack of BRAF mutation but occurrence of RET/PTC rearrangements

et al. 2007

Diffuse sclerosing variant of papillary thyroid carcinoma (PTC) is a rare tumour with a characteristic morphology as well as a strong preponderance for younger female patients. The T1799A missense mutation in exon 15 of the BRAF gene and RET/PTC rearrangement have been identified as the dominant genetic tumour initiation events in the pathogenesis of PTC leading to a constitutive activation of the RAS-RAF-MAPK pathway. In order to elucidate the pathogenesis of diffuse sclerosing variant of PTC, the prevalence of BRAF mutation and RET/PTC were determined by RT-polymerase chain reaction and DNA-sequence analysis in tumour samples of seven patients with this variant (all female, age range 15-61 years, mean 33.3 years) without prior radiation exposure. None of these cases showed a BRAF mutation. RET/PTC1 (two out of seven) and RET/PTC3 (one out of seven), which have been shown in large PTC series to comprise together more than 90% of RET/PTC types, were found in o50% of the cases investigated. All seven samples expressed the RET tyrosine kinase domain but lacked its extracellular domain potentially suggesting the existence of rare types of RET/PTC rearrangement in the four remained cases of diffuse sclerosing variant of PTC. Regarding this subtype, our study confirmed the paradigm of a mutual exclusivity between RET/PTC and BRAF in PTC. Additionally, this rare variant of papillary thyroid carcinoma may represent a tumour type susceptible to RET-targeted therapies.