BRAF Mutation In Thyroid Cancer Research Articles

Association of DNA Promoter Methylation and BRAF Mutation in Thyroid Cancer.

The BRAF V600E mutation and DNA promoter methylation play important roles in the pathogenesis of thyroid cancer (TC). However, the association of these genetic and epigenetic alterations is not clear. In this study, using paired tumor and surrounding normal tissue from the same patients, on a genome-wide scale we tried to identify (a) any association between BRAF mutation and DNA promoter methylation, and (b) if the molecular findings may provide a basis for therapeutic intervention. We included 40 patients with TC (female = 28, male = 12) without distant metastasis. BRAF mutation was present in 18 cases. We identified groups of differentially methylated loci (DML) that are found in (a) both BRAF mutant and wild type, (b) only in BRAF mutant tumors, and (c) only in BRAF wild type. BRAF mutation-specific promoter loci were more frequently hypomethylated, whereas BRAF wild-type-specific loci were more frequently hypermethylated. Common DML were enriched in cancer-related pathways, including the mismatch repair pathway and Wnt-signaling pathway. Wild-type-specific DML were enriched in RAS signaling. Methylation status of checkpoint signaling genes, as well as the T-cell inflamed genes, indicated an opportunity for the potential use of PDL1 inhibitors in BRAF mutant TC. Our study shows an association between BRAF mutation and methylation in TC that may have biological significance.

Artificial intelligence for disease diagnosis: the criterion standard challenge

Artificial intelligence for disease diagnosis: the criterion standard challenge

BRAF mutations in thyroid cancer.

Activating mutations in the mitogen-activated protein kinase (MAPK) pathway play an important role in papillary (PTC) and anaplastic (ATC) thyroid cancer. The aim of this review is to discuss the impact of BRAF mutations on clinical features and treatment of patients with thyroid cancer. Despite the unfavorable course associated with PTCs harboring BRAF V600E mutation, its prognostic role remains debated. BRAF V600E-driven tumors exhibit high Extracellular signal-regulated kinase phosphorylation, leading to unregulated cell proliferation and inhibition of the required genes for radioiodine responsiveness in thyroid cancer. The mechanism associated with the variable BRAF-mutant tumor aggressiveness remains unclear and other pathways are likely to co-operate to promote cancer progression. Overexpression of the Notch signaling and loss of individual switch/ sucrose non-fermentable chromatin-remodeling complexes subunits might be involved. The combination of the BRAF inhibitor dabrafenib and the mitogen-activated protein kinase kinase inhibitor trametinib has shown remarkable results in clinical trials of patients with BRAF-mutated ATCs. The impact of BRAF mutations on the clinical outcomes of PTC remains debatable. In ATCs, in turn, BRAF mutations identify patients eligible for targeted therapy, which is now considered in two settings: as neoadjuvant for unresectable tumors and as a treatment for metastatic or unresectable disease.

Precision medicine: BRAF mutations in thyroid cancer

Mutations in BRAF are commonly seen in thyroid carcinoma and can have therapeutic and prognostic implications. The BRAF V600E mutation is seen in approximately 40% of cases of papillary thyroid carcinoma (PTC), and is associated with aggressive clinicopathological features, higher recurrence rate, and disease related mortality. Significant advances have occurred in the development of new therapeutic targets of the MAP kinase pathway, which is activated in the setting of BRAF mutations, including BRAF and mitogen extracellular kinase (MEK) inhibitors. BRAF alterations other than V600E are less common in PTC, and their clinical significance remains to be established. Here we present a case of a male with poorly differentiated thyroid carcinoma, with papillary and follicular features, who was noted to have a BRAF K601E mutation. The patient was subsequently treated with a BRAF inhibitor, dabrafenib, and MEK inhibitor, trametinib.

Utility of the BRAF p.V600E immunoperoxidase stain in FNA direct smears and cell block preparations from patients with thyroid carcinoma.

The identification of BRAF mutations in thyroid cancer has prognostic and therapeutic implications. Although the gold standard for identifying BRAF mutations is molecular testing, the ability to perform BRAF p.V600E immunostaining on fine-needle aspiration (FNA) samples can facilitate the rapid triaging of patients to treatment options. A total of 50 thyroid carcinoma FNA samples, including papillary (29 samples), poorly differentiated (10 samples), anaplastic (9 samples), and Hurthle cell (2 samples) carcinomas, with a known BRAF p.V600E mutation status were selected for the current study. Immunostaining was performed on smears and cell block sections using an anti-BRAF p.V600E antibody (clone VE1). The results were compared with the known mutation status obtained by molecular testing and/or immunostaining of surgical pathology material from the same patient. Of the total of 50 cases, 26 cases had smears available for the evaluation of BRAF p.V600E immunostaining; positive immunostaining was noted in 16 samples and negative immunostaining was noted in 4 samples, whereas 6 cases were equivocal. Of the 34 cases for which cell blocks were available for evaluation, BRAF p.V600E immunostaining was positive in 17 cases, negative in 16 cases, and equivocal in 1 case. The overall sensitivity and specificity of BRAF p.V600E immunostaining on the cell block preparation was 94.4% and 100%, respectively, whereas for the smears it was 80% and 63.6%, respectively. BRAF p.V600E immunostaining can be performed reliably on thyroid FNA cell block preparations. However, false-positive results on direct smears limit their utility and therefore need to be interpreted with caution. Cancer Cytopathol 2018;126:406-13. © 2018 American Cancer Society.

Abstract 5186: Vemurafenib selectively radiosensitizes BRAF V600E mutant papillary and anaplastic thyroid carcinoma cells

Abstract BRAF activating mutations act as oncogenic drivers and are highly prevalent in thyroid cancer, occurring in about 60% of papillary thyroid cancer (PTC) as well as 30-40% anaplastic thyroid cancer (ATC). MAPK signaling and treatment resistance is driven by BRAF mutations in thyroid cancer. Among the most common of these mutations is BRAFV600E, which can be selectively inhibited by vemurafenib. Using a panel of PTC and ATC cell lines we assessed how the presence/absence of BRAFV600E impacts radiation sensitivity. We used radiation clonogenics, comet assays, nuclear foci formation, immunoblotting, and mouse xenografts models to determine the effect of vemurafenib on PTC and ATC cells. Analysis of radiation clonogenics implicated higher radioresistance in cell lines containing the BRAFV600E mutation as compared to wild-type BRAF. Additionally, forced expression of BRAFV600E in a wild-type thyroid cancer cell line induced radioresistance. Vemurafenib inhibited MAPK signaling in V600E mutant cell lines, but showed no effect in BRAF wild-type cell lines. Vemurafenib pretreatment selectively radiosensitized BRAFV600E mutants in vitro, as assessed by radiation clonogenic assays. Comet assays revealed impairment of DNA repair in BRAFV600E lines when treated with vemurafenib and radiation. Additionally, γ-H2A.x westerns and nuclear foci staining indicated that vemurafenib pretreatment decreases the tumor cell’s ability to repair DNA double-strand breaks (DSB) in BRAFV600E cell lines. Vemurafenib also appeared to alter the kinetics of formation and resolution of 53BP1 and Rad51 nuclear foci in these cell lines. Evaluation of DSB functional repair using GFP reporter constructs, suggests that BRAFV600E induces NHEJ repair, which can be attenuated by vemurafenib treatment. Finally, vemurafenib effectively increases radiosensitivity of BRAF V600E tumors in vivo. From our results, BRAF activating mutation appears to be associated with radioresistance. Vemurafenib selectively radiosensitizes both PTC and ATC cells through inhibition of DNA repair mechanisms. Combining vemurafenib and radiation may improve therapeutic control for BRAFV600E mutant thyroid cancers. Citation Format: Ryan N. Robb, Linlin Yang, Terence Williams. Vemurafenib selectively radiosensitizes BRAF V600E mutant papillary and anaplastic thyroid carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5186. doi:10.1158/1538-7445.AM2017-5186

Clinical Implication of BRAF Mutation in Thyroid Cancer

Clinical Implication of BRAF Mutation in Thyroid Cancer

Clinicopathological features of rare BRAF mutations in Korean thyroid cancer patients.

The most common BRAF mutation in thyroid cancer is c.1799T>A (p.Val600Glu), and other BRAF mutations are rarely reported. We investigated the clinicopathological features of thyroid cancer with rare BRAF mutations. A total of 2,763 patients with thyroid cancer underwent molecular testing by direct DNA sequencing for mutations in BRAF exon 15. Among them, 2,110 (76.4%) had BRAF mutations. The c.1799T>A mutation was found in 2,093 (76.9%) of 2,722 papillary carcinomas and in one of 7 medullary carcinomas. Sixteen cases (0.76%) harbored rare mutation types. Five cases had single-nucleotide substitutions, 5 cases had small in-frame deletion or insertion, and one harbored a two-nucleotide substitution. Of these mutations, 2 were novel (c.1797_1798insGAGACTACA, c.[1799T>A; 1801_1812del]). The c.1801A>C mutation was identified in 4 follicular variant papillary carcinomas and one follicular carcinoma. None of the patients with the c.1801A>C mutation showed extrathyroidal extension or lymph node metastasis. The prevalence of rare BRAF mutations was 0.76% of all BRAF-positive thyroid cancers, and the rare mutations were associated with less aggressive pathologic features. Although BRAF mutations are detected exclusively in papillary carcinoma, they are also found in medullary carcinoma and follicular carcinoma.Graphical

Thyroid cancer genetics: how close are we to personalizing clinical management?

Author for correspondence: Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA and Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Thyroid Cancer Center, Endocrinology & Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Stanley Shalom Zielony Institute of Nursing Excellence, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Genetics, & CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA Tel.: +1 216 444 3440 Fax: +1 216 636 0655 engc@ccf.org Thyroid cancer genetics: how close are we to personalizing clinical management?

Epigenetic Regulation ofRUNX3in Thyroid Carcinoma

Epigenetic Regulation of<i>RUNX3</i>in Thyroid Carcinoma

Prognostic utility of BRAF mutation in thyroid cancer

Prognostic utility of BRAF mutation in thyroid cancer

Prognostic utility of BRAF mutation in thyroid cancer

Prognostic utility of BRAF mutation in thyroid cancer

Spry2 expression correlates with BRAF mutation in thyroid cancer

BRAF mutations activate the mitogen-activated protein kinase pathway and often confer an aggressive thyroid cancer (TC) phenotype. Spry2 is an inducible negative feedback regulator of the mitogen-activated protein kinase (MAPK) pathway. The aim of this study was to investigate the role of Spry2 in TC. TC cell lines were analyzed for Spry2 expression and MAPK pathway activation. Cells were treated with MEK inhibitor and Spry2 small hairpin RNA. Cells were analyzed for Spry2 expression and MEK/ERK phosphorylation (pMEK, pERK). Thirty human papillary TCs were analyzed for mitogen-activated protein kinase pathway activating mutations and Spry2 expression. Increased baseline pMEK levels and Spry2 expression was found in BRAF V600E mutant (BRAF+) cells. MEK inhibition in BRAF+ cells showed decreased Spry2 expression and decreased pMEK/pERK levels. From our tissue samples, 10 papillary TCs had BRAF mutation, and increased Spry2 expression was found only in BRAF+ tumors. Spry2 expression correlates with BRAF status in vitro and in human tissue. Spry2 may serve as a negative feedback regulator of the mitogen-activated protein kinase pathway in BRAF+ TC. Increased Spry2 expression may serve as a surrogate marker of mitogen-activated protein kinase pathway activation with prognostic and therapeutic implications.

The Prevalence and Prognostic Value of BRAF Mutation in Thyroid Cancer

To examine the prevalence of BRAF mutation among thyroid cancer histologic subtypes and determine the association of BRAF mutation with indicators of poor prognosis for papillary thyroid cancer and patient outcome. The appropriate extent of surgical treatment, adjuvant therapy and follow-up monitoring for thyroid cancer remains controversial. Advances in the molecular biology of thyroid cancer have helped to identify candidate markers of disease aggressiveness. A commonly found genetic alternation is a point mutation in the BRAF oncogene (BRAF V600E), which is primarily found in papillary thyroid cancer and is associated with more aggressive disease. BRAF V600E mutation status was determined in 347 tumor samples from 314 patients with thyroid cancer (245 with conventional papillary thyroid cancer, 73 with follicular thyroid cancer, and 29 with the follicular variant of papillary thyroid cancer). Univariate and multivariate analyses were performed to determine the association of BRAF V600E with clinicopathologic factors and patient outcome. : The prevalence of BRAF V600E mutation was higher in conventional papillary thyroid cancer (51.0%) than in follicular variant of papillary thyroid cancer (24.1%) and follicular thyroid cancer (1.4%) (P < 0.0001). In patients with conventional papillary thyroid cancer, BRAF V600E mutation was associated with older age (P = 0.0381), lymph node metastasis (P = 0.0323), distant metastasis (P = 0.045), higher TNM stage (I and II vs. III and IV, P = 0.0389), and recurrent and persistent disease (P = 0.009) with a median follow-up time of 6.0 years. Multivariate analysis showed that BRAF V600E mutation [OR (95% CI) = 4.2 (1.2-14.6)] and lymph node metastasis [OR (95% CI) = 7.75 (2.1-28.5)] were independently associated with recurrent and persistent disease in patients with conventional papillary thyroid cancer. BRAF V600E mutation is primarily present in conventional papillary thyroid cancer. It is associated with an aggressive tumor phenotype and higher risk of recurrent and persistent disease in patients with conventional papillary thyroid cancer. Testing for this mutation may be useful for selecting initial therapy and for follow-up monitoring.

BRAF mutation in thyroid cancer

Genetic alteration is the driving force for thyroid tumorigenesis and progression, based upon which novel approaches to the management of thyroid cancer can be developed. A recent important genetic finding in thyroid cancer is the oncogenic T1799A transversion mutation of BRAF (the gene for the B-type Raf kinase, BRAF). Since the initial report of this mutation in thyroid cancer 2 years ago, rapid advancements have been made. BRAF mutation is the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic papillary thyroid cancers (PTCs), particularly in the relatively aggressive subtypes, such as the tall-cell PTC. This mutation is mutually exclusive with other common genetic alterations, supporting its independent oncogenic role, as demonstrated by transgenic mouse studies that showed BRAF mutation-initiated development of PTC and its transition to anaplastic thyroid cancer. BRAF mutation is mutually exclusive with RET/PTC rearrangement, and also displays a reciprocal age association with this common genetic alteration in thyroid cancer. The T1799A BRAF mutation occurs exclusively in PTC and PTC-derived anaplastic thyroid cancer and is a specific diagnostic marker for this cancer when identified in cytological and histological specimens. This mutation is associated with a poorer clinicopathological outcome and is a novel independent molecular prognostic marker in the risk evaluation of thyroid cancer. Moreover, preclinical and clinical evaluations of the therapeutic value of novel specific mitogen-activated protein kinase pathway inhibitors in thyroid cancer are anticipated. This newly discovered BRAF mutation may prove to have an important impact on thyroid cancer in the clinic.

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.