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Lee, Min Hee, Seong Eun Lee, Dong Wook Kim, Min Jeong Ryu, Sung Jin Kim, Sung Joong Kim, Yong Kyoung Kim, et al. "Mitochondrial Localization and Regulation of BRAFV600E in Thyroid Cancer: A Clinically Used RAF Inhibitor Is Unable to Block the Mitochondrial Activities of BRAFV600E." Journal of Clinical Endocrinology & Metabolism 96, no. 1 (January 1, 2011): E19—E30. http://dx.doi.org/10.1210/jc.2010-1071.
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Context: The oncogenic BRAFV600E mutation results in an active structural conformation characterized by greatly elevated ERK activity. However, additional cellular effects caused by subcellular action of BRAFV600E remain to be identified. Objective: To explore these effects, differences in the subcellular localization of wild-type and mutant BRAF in thyroid cancer were investigated. Results: A significant proportion of endogenous and exogenous BRAFV600E, but not wild-type BRAF, was detected in the mitochondrial fraction, similar to other BRAF mutants including BRAFV600D, BRAFV600K, BRAFV600R, and BRAFG469A, which showed elevated kinase activity and mitochondrial localization. Induced expression of BRAFV600E suppressed the apoptotic responses against staurosporine and TNFα/cycloheximide. Interestingly, the mitochondrial localization and antiapoptotic activities of BRAFV600E were unaffected by sorafenib and U0126 suppression of MAPK kinase (MEK) and ERK activities. Similarly, although the RAF inhibitor sorafenib effectively inhibited MEK/ERK activation, it did not block the mitochondrial localization of BRAFV600E. In addition, inducible expression of BRAFV600E increased the glucose uptake rate and decreased O2 consumption, suggesting that BRAFV600E reduces mitochondrial oxidative phosphorylation, a signature feature of cancer cells. Again, these metabolic alterations resulted by BRAFV600E expression were not affected by the treatment of thyroid cells by sorafenib. Therefore, RAF and MEK inhibitors are unable to block the antiapoptotic activity of BRAFV600E or correct the high glucose uptake rate and glycolytic activity and suppressed mitochondrial oxidative phosphorylation induced by BRAFV600E. Conclusions: The mitochondrial localization observed in oncogenic BRAF mutants might be related to their altered responses to apoptotic stimuli and characteristic metabolic phenotypes found in thyroid cancer. The inability of MEK and RAF inhibitors, U0126 and sorafenib, respectively, to block the mitochondrial localization of BRAFV600E has additional therapeutic implications for BRAFV600E-positive thyroid cancers.
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Sahm, Felix, David Capper, Matthias Preusser, Jochen Meyer, Albrecht Stenzinger, Felix Lasitschka, Anna-Sophie Berghoff, et al. "BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis." Blood 120, no. 12 (September 20, 2012): e28-e34. http://dx.doi.org/10.1182/blood-2012-06-429597.
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AbstractLangerhans cell histiocytosis (LCH) is a clinically and histologically heterogeneous disorder. Its classification as either reactive inflammatory or neoplastic has been a matter of debate. However, the recent finding of frequent BRAFV600E mutations in LCH argues for the latter. The exact cell type that harbors the mutation and is responsible for proliferation remains to be identified. We here apply a BRAFV600E mutation-specific antibody to detect the BRAF mutant cells in lesions from 89 patients with LCH. We found BRAFV600E mutations in 34 of 89 (38%) lesions. In lesions with the BRAFV600E mutation, the majority of cells coexpressing S-100 and CD1a harbored mutant BRAFV600E protein. These cells also expressed CD14 and CD36, whereas various fractions exhibited CD207. On the other hand, CD80 and CD86 expression was also present on BRAFV600E-positive cells. Thus, cells of variable maturation, exhibiting an immunohistochemical profile compatible either with myeloid cell or with dedifferentiated Langerhans cell antigens, carry the BRAFV600E mutation. In conclusion, we identify and characterize the neoplastic cells in LCH with BRAFV600E mutations by applying a mutation-specific marker and demonstrate feasibility for routine screening.
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Chakraborty, Dhritiman, Sunil Shakya, Sanjana Ballal, Shipra Agarwal, and Chandrasekhar Bal. "BRAFV600E and TERT promoter mutations in paediatric and young adult papillary thyroid cancer and clinicopathological correlation." Journal of Pediatric Endocrinology and Metabolism 33, no. 11 (November 26, 2020): 1465–74. http://dx.doi.org/10.1515/jpem-2020-0174.
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AbstractObjectivesThe primary objective of this study was to determine the prevalence of BRAFV600E and TERTpromoter mutations in paediatric and young adult patients with papillary thyroid carcinoma (PTC) and the secondary objective, to assess their association with clinicopathological features.MethodsPatients ≤20 years who underwent surgery for differentiated thyroid cancer (DTC) from 2005 to 2018 were consecutively enrolled for BRAFV600E and TERTpromoter mutations analysis and records analysed for the association of aggressive features. Univariate analysis and multivariate logistic regression were used to identify the independent predictors of BRAFV600E mutations.ResultsAmong 100 patients with DTC, 68 patients were ≤18 years and the remaining 30 patients were >18 years of age with a median age of 17 years (IQR 14–19 years) 98 patients had PTC and 2 had FTC. BRAFV600E mutation was present in 14/98 (14.3%) PTC and TERTpromoter mutation noted in none. Multivariate analysis identified RAI refractoriness (OR:10.57, 95% CI: 2.6 to 41.6, P-0.0008) as an independent factor associated with BRAFV600E mutation. 17 patients with distant metastases were negative for both BRAFV600E or TERTpromoter mutation. No significant association was observed between age, gender, PTC variants, extra-thyroidal extension, lymphovascular invasion, multifocality, RAI administration and event rate with BRAFV600E mutation. Irrespective of BRAFV600E mutation, radioiodine refractory status (p-0.0001) had a reduced EFS probability.ConclusionIn paediatric & young adult PTC, TERTpromoter mutation is absent and BRAFV600E mutation is not associated with distant metastasis. The prevalence rate of the BRAFV600E mutation is much lower compared to adult PTC patients.
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Diamond, Eli L., Benjamin Durham, Ahmet Dogan, Mariko Yabe, Kseniya Petrova-Drus, Raajit K. Rampal, Raajit K. Rampal, et al. "Phase 2 Trial of Single-Agent Cobimetinib for Adults with Histiocytic Neoplasms." Blood 142, Supplement 1 (November 28, 2023): 1812. http://dx.doi.org/10.1182/blood-2023-187508.
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Background: Histiocytic neoplasms (HN) are clonal hematopoietic disorders characterized by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway. BRAF inhibition is highly effective for patients with HN harboring the BRAFV600E mutation, and implementation of BRAF inhibitors transformed management of BRAFV600E-mutated Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH). No standard or approved therapies existed, however, for patients with HN lacking the BRAFV600E mutation. Efficacy of mitogen-activated protein kinase (MEK) inhibition for HN harboring various MAPK pathway mutations has been observed in case reports and series. We present here results from 26 patients treated in a phase 2 trial of single-agent cobimetinib for adults with HN (NCT02649972). The data were submitted to the Food and Drug Administration (FDA) in a supplemental new drug application for cobimetinib, and FDA approval was granted in October, 2022. Methods: This is an open-label phase 2 trial of cobimetinib 60mg daily for patients with (1) BRAFV600-wildtype (wt) histiocytosis or (2) BRAFV600-mutant histiocytosis intolerant or without access to BRAF inhibitor therapy. Eligible patients were age 16 or older, had histologic confirmation of HN diagnosis, ECOG 0 to 3, multi-system HN or HN refractory to conventional (i.e. chemotherapeutic or immunosuppressive) therapy or single-system HN deemed unlikely to benefit from conventional therapy, and with disease measurable by positron emission tomography (PET) Response Criteria (PRC). Patients were eligible with any tumor mutation or with no identified tumor mutation. The primary endpoint was overall response rate (complete metabolic response + partial metabolic response; ORR) by PRC. Secondary endpoints included safety (CTCAE 4.0), duration of response (DoR) and progression-free survival (PFS) as determined by modified PERCIST, overall survival (OS), and response rate by RECIST. Data cut-off was March 28, 2019 for efficacy evaluation, and safety follow-up cut-off was September 28, 2019. Results: Twenty-six patients (13 ECD, with Rosai-Dorfman disease [RDD], 4 with LCH, 2 with juvenile xanthogranuloma [JXG], 3 with mixed histiocytosis) with a median age of 50.5 were analyzed. Six patients had BRAFV600E-mutant disease, one of these with additional mutations in KRAS and NRAS. Of the remaining 20, 15 had non-BRAFV600 MAPK pathway mutations (4 KRAS [one of them with ARAF mutation as well], 6 MEK1, 1 MEK2, 1 RAF1, 1 ARAF, 2 non-V600 BRAF mutations, and 5 had no mutation identified). Twenty-six patients were evaluable for safety, 24 for PRC, 19 for RECIST. Response rates are listed in Table 1 and PRC responses are presented in Figure 1. The ORR by PRC was 83.3% (95% CI 62.62-95.26), in the PRC-evaluable population. Responses were observed across MAPK mutations, histiocytosis subtypes and tumor genotypes. By BRAFV600 status, in PRC-evaluable population, the ORR for BRAFV600E-mutant disease was 100% (95% CI 47.82-100), and for BRAFV600-wt disease was 78.9% (95% CI 54.43-93.95). Median DoR was 31.1 months (95% CI 16.8-NE) in the PRC-evaluable population. ORR by RECIST was 63.2% (95% CI 38.36-83.71), in the RECIST-evaluable population. Three patients died on study, none related to cobimetinib. Grade 3 or 4 toxicities in >10% of patients included decreased lymphocyte count (19%), increased blood creatine phosphokinase (12%), decreased ejection fraction (12%), hypokalemia (12%), hyponatremia (12%), acute kidney injury (12%) and dyspnea (12%). Conclusions: Cobimetinib demonstrates robust efficacy in HN irrespective of underlying MAPK pathway mutation, including BRAF-wt and BRAFV600-mutant HN. Safety of cobimetinib in this patient population was consistent with the known safety profile.
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Song, Eyun, Meihua Jin, Ahreum Jang, Min Ji Jeon, Dong Eun Song, Hye Jin Yoo, Won Bae Kim, Young Kee Shong, and Won Gu Kim. "Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAFV600E-Mutant Advanced Papillary Thyroid Carcinoma." Cancers 13, no. 22 (November 22, 2021): 5846. http://dx.doi.org/10.3390/cancers13225846.
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The prognosis of BRAFV600E-mutant papillary thyroid carcinoma (PTC) ranges from indolent to highly aggressive courses. To better define the genetic diversity of this subtype, we evaluated the survival according to the presence of an additional mutation in genes encoding functional groups (FGs) in BRAFV600E-mutant advanced PTC patients. Targeted next-generation sequencing was performed in primary tumors of 50 BRAFV600E-mutant PTCs with distant metastasis or aggressive variants. The mutation in genes encoding FGs included alterations in histone methyltransferases, SWI/SNF subunit, and the PI3K/AKT/mTOR pathway. The primary outcome was overall survival (OS). Fifteen patients only had the BRAFV600E-mutation (group 1), 22 had BRAFV600E and mutation other than FGs (group 2), and 13 had BRAFV600E and FG mutation (group 3). OS was significantly lower in patients with FG mutations (p = 0.001) than those without, and group 3 patients had the worst survival (p = 0.004). OS significantly varied among none, one, or two FG mutation sites (p = 0.005). Presence of FG mutation was independently associated with increased mortality (hazard ratio 11.65, 95% confidence interval 1.39–97.58, p = 0.024). Coexistence of mutations in BRAFV600E and genes encoding FGs was associated with high mortality. Identification of FG mutation in BRAFV600E-mutant PTCs may be valuable in risk stratifying this subtype.
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Kaneko, Masanao, Mitsuko Nakashima, Kiichi Sugiura, Natsuki Ishida, Satoshi Tamura, Shinya Tani, Mihoko Yamade, et al. "Both MLH1 deficiency and BRAFV600E mutation are a unique characteristic of colorectal medullary carcinoma: An observational study." Medicine 102, no. 38 (September 22, 2023): e35022. http://dx.doi.org/10.1097/md.0000000000035022.
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Although immunohistochemistry (IHC) for mismatch repair (MMR) proteins (MMR IHC) is used to identify DNA MMR status, universal screening of all patients with colorectal cancer (CRC) using a combination of both MMR IHC and genetic testing for the BRAFV600E mutation is limited in Japan. This study aimed to better understand the histopathological characteristics of CRCs, which exhibit both deficient mismatch repair (dMMR) and BRAFV600E mutation. MMR IHC of formalin-fixed paraffin-embedded tissues from tumor areas obtained from 651 patients with CRC who underwent surgical resection at Hamamatsu University Hospital (Hamamatsu, Japan) between August 2016 and March 2022 were used to evaluate MMR status, which was determined by staining for the expression of 4 MMR proteins (MLH1, MSH2, PMS2, and MSH6). All dMMR tumors were additionally evaluated for BRAFV600 mutation status via Sanger sequencing. Patient clinical characteristics (age, sex, tumor location, size, and tumor pathology) were then classified using their dMMR and BRAFV600 mutation statuses. Among the 651 patients with CRC, 58 carried tumors with dMMR, of which 52 were deficiency in MLH1 (dMLH1). Interestingly, all 16 medullary carcinomas that were analyzed showed characteristics corresponding to the presence of both dMLH1 and BRAFV600E mutation (P = .01). These results suggest that colorectal medullary carcinomas can be diagnosed based on their unique characteristics of harboring the BRAFV600E mutation and exhibiting dMLH1 expression.
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Ascierto, Paolo A., David Minor, Antoni Ribas, Celeste Lebbe, Anne O'Hagan, Niki Arya, Mary Guckert, et al. "Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma." Journal of Clinical Oncology 31, no. 26 (September 10, 2013): 3205–11. http://dx.doi.org/10.1200/jco.2013.49.8691.
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Purpose Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAFV600E/K mutation–positive metastatic melanoma (mut+ MM). Patients and Methods Histologically confirmed patients with stage IV BRAFV600E/K mut+ MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAFV600E mut+ MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome. Results Seventy-six patients with BRAFV600E and 16 patients with BRAFV600K mut+ MM were enrolled onto the study. In the BRAFV600E group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAFV600K mut+ MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAFV600E and BRAFV600K groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAFV600E mut+ MM patients. Conclusion Dabrafenib was well tolerated and clinically active in patients with BRAFV600E/K mut+ MM. cfDNA may be a useful prognostic and response marker in future studies.
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Morris, Van K., Kanwal Pratap Singh Raghav, Arvind Dasari, Michael J. Overman, Bryan K. Kee, Benny Johnson, Christine Megerdichian Parseghian, et al. "Utility of circulating tumor DNA in the clinical management of patients with BRAFV600E metastatic colorectal cancer." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 119. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.119.
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119 Background: Molecular profiling is critical for oncologists in personalizing treatment decisions for patients (pts) with metastatic colorectal cancer (mCRC). In contrast to archival tumor tissue specimens classically used profiling, sequencing of circulating tumor DNA (ctDNA) is more sensitive at quantifying low mutation allele frequencies and characterize “real time” tumor biology. We assessed the relationship between detection of BRAFV600E mutations in ctDNA and the clinical management of pts with mCRC. Methods: We retrospectively analyzed mCRC patients evaluated at MD Anderson Cancer Center with BRAFV600E mutations on ctDNA. ctDNA was isolated and sequenced for somatic mutations using a 70-gene next-generation sequencing assay (MD Anderson/GuardantHealth LB70 panel). Variant allele frequency (VAF) was characterized as the ratio of mutant reads: total reads for a given gene. BRAFV600E mutations were classified as “clonal” if the relative VAF (rVAF) exceeded 50% of the maximum VAF. “Major” and “minor” subclonal mutations were called for a rVAF of 10-50% and < 10%, respectively. Associations between BRAFV600E clonality and treatment decision were performed using a Fisher’s exact test. Survival outcomes were estimated using the Kaplan-Meier method. Results: 64 patients with mCRC had a BRAFV600E mutation detected in ctDNA. Concordance between tissue and ctDNA for BRAFV600E mutation was occurred in 44/55 (80%) patients with evaluable tumor specimen. There were 9 patients with BRAFV600E mutations identified in the absence of evaluable tumor tissue. Median VAF for BRAFV600E in the ctDNA was 3.6% (interquartile range, 0.50 – 17%). The majority of patients had a clonal BRAFV600E mutation (50/64, 78%). There were 3 (5%) and 11 (17%) patients with major subclonal and minor subclonal BRAFV600E mutations, respectively. Among patients with minor subclonal BRAFV600E mutations, 91% (10/11) had developed resistance to anti-EGFR therapies for management of RASwild-type mCRC. Discordance between tissue and ctDNA BRAFV600E status was associated with minor subclones (odds ratio (OR) 56, p < .0001). Clonal BRAFV600E mutations in the ctDNA were associated with a higher likelihood for treatment with BRAF targeted therapies (OR 5.8, p = .008). Median progression-free survival among 37 evaluable patients was 6.4 months. Conclusions: Reported VAF in the ctDNA served to stratify BRAFV600E according to relative clonality. Lower VAF was linked to acquired resistance to anti-EGFR therapies, whereas higher VAF was associated with receipt of matched targeted therapies for BRAFV600E mCRC. ctDNA technologies for identifying BRAFV600E mutations are feasible and informative for conducting relevant molecular profiling for patients with mCRC.
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Smyrk, Thomas C., David Tougeron, Stephen N. Thibodeau, Shalini Singh, Andrea Muranyi, Kandavel Shanmugam, Thomas M. Grogan, Steven R. Alberts, Qian Shi, and Frank A. Sinicrope. "Detection of the BRAFV600E protein in human colon carcinomas by a mutation-specific antibody." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 3576. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3576.
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3576 Background: BRAF encodes a serine-threonine kinase that is a downstream effector of activated RAS. A point mutation (V600E) in BRAF occurs in a subset of colorectal cancers (CRCs) and is associated with adverse outcome and may predict non response to anti-EGFR antibodies. Detection of a BRAFV600E mutation in a CRC with microsatellite instability indicates a sporadic origin and excludes Lynch Syndrome. While BRAFV600E mutation status is determined using a DNA-based assay, antibodies against the BRAFV600E protein have recently been developed. We examined mutant BRAFV600E protein expression and its concordance with mutation status. Methods: Primary stage III colon carcinomas (50 BRAFV600E mutation carriers and 25 wild-type cases) were studied from a completed phase III adjuvant trial comparing FOLFOX +/- cetuximab (NCCTG N0147). In archival resection specimens, immunohistochemistry (IHC) was performed using a pan-BRAF antibody and a V600E mutation-specific antibody raised against an immunogenic synthetic peptide derived from the internal region of the BRAFV600E protein. BRAFV600E mutations in codon 15 were analyzed in extracted DNA using a multiplex, allele specific PCR–based assay. BRAF staining was scored independently by two pathologists blinded to mutation status. Results: In primary colon carcinomas stained with a pan-BRAF antibody, diffuse cytoplasmic staining for BRAF proteins was detected in 74 of 75 carcinomas with one case deemed non-evaluable. Using the mutation-specific BRAFV600E antibody, diffuse cytoplasmic staining was detected in 49 of 74 tumors without appreciable heterogeneity of expression. Among these 49 tumors expressing mutant BRAFV600E proteins, all (100%) were found to carry a BRAFV600E mutation according to a DNA-based assay. In contrast, absent BRAFV600E staining was observed in all 25 tumors that were found to have wild-type copies of BRAFV600E detected using a PCR-based assay. Conclusions: For the detection of mutant BRAFV600E, complete concordance was found between IHC and a DNA-based method in colon carcinomas. This finding supports the use of IHC as a simplified strategy to screen CRCs for mutant BRAFV600E proteins in routine clinical practice to inform clinical decision-making.
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Choi, Yun-Suk, Seong-Woon Choi, and Jin-Wook Yi. "Prospective Analysis of TERT Promoter Mutations in Papillary Thyroid Carcinoma at a Single Institution." Journal of Clinical Medicine 10, no. 10 (May 18, 2021): 2179. http://dx.doi.org/10.3390/jcm10102179.
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Background: Papillary thyroid cancer (PTC) has the highest cancer incidence in Korea. It is known that some thyroid cancers have aggressive clinical behavior and a poor prognosis. Genomic studies have described some somatic mutations that are related to the aggressive features of thyroid cancer, such as the BRAFV600E mutation. Recently, TERT promoter mutations were identified and reported as poor prognostic factors in PTC. Our aim was to identify the frequency and clinical impact of TERT promoter mutation in PTC. Methods: Analysis of both BRAFV600E and TERT promoter mutations in thyroidectomy specimens began in February 2019. As of December 2020, 622 patients had been tested. Data were prospectively collected and retrospectively reviewed to ascertain clinical and pathologic variables. Results: TERT promoter mutations were identified in 13 patients (2.09%); 12 had the C228T mutation, and one had the C216T mutation. In total, ten patients had the BRAFV600E mutation. TERT promoter mutation was significantly associated with advanced age (46.795 ± 12.616 versus 65.692 ± 13.628 years, p < 0.001), large tumor size (1.006 ± 0.829 versus 2.285 ± 1.938 cm, p = 0.035), extrathyroidal extension, surgical margin involvement, angioinvasion, BRAFV600E mutation and advanced TNM stage, a higher MACIS score and a high proportion of radioactive iodine therapy application. Logistic regression showed that lymphatic and angioinvasion and BRAFV600E mutation were predictive of TERT promoter mutation. Conclusions: Our study is the first to report the prospective results of TERT promoter mutations at a single tertiary hospital in Incheon, Korea. PTC with TERT promoter mutation was associated with more aggressive behavior than PTC with wild-type TERT gene status.
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Song, Young Shin, Seong-Keun Yoo, Hwan Hee Kim, Gyeongseo Jung, Ah-Reum Oh, Ji-Young Cha, Su-jin Kim, et al. "Interaction of BRAF-induced ETS factors with mutant TERT promoter in papillary thyroid cancer." Endocrine-Related Cancer 26, no. 6 (June 2019): 629–41. http://dx.doi.org/10.1530/erc-17-0562.
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Synergistic effects of BRAFV600E and TERT promoter mutations on the poor clinical outcomes in papillary thyroid cancer (PTC) have been demonstrated. The potential mechanism of this phenomenon has been proposed: MAPK pathway activation by the BRAFV600E mutation may upregulate E-twenty six (ETS) transcription factors, increasing TERT expression by binding to the ETS-binding site generated by the TERT promoter mutation; however, it has not yet been fully proven. This article provides transcriptomic insights into the interaction between BRAFV600E and TERT promoter mutations mediated by ETS factors in PTC. RNA sequencing data on 266 PTCs from The Cancer Genome Atlas and 65 PTCs from our institute were analyzed for gene expression changes and related molecular pathways, and the results of transcriptomic analyses were validated by in vitro experiments. TERT mRNA expression was increased by the coexistence of BRAFV600E and TERT promoter mutations (fold change, 16.17; q-value = 7.35 × 10−12 vs no mutation). In the ETS family of transcription factors, ETV1, ETV4 and ETV5 were upregulated by the BRAFV600E/MAPK pathway activation. These BRAFV600E-induced ETS factors selectively bound to the mutant TERT promoter. The molecular pathways activated by BRAFV600E were further augmented by adding the TERT promoter mutation, and the pathways related to immune responses or adhesion molecules were upregulated by TERT expression. The mechanism of the synergistic effect between BRAFV600E and TERT promoter mutations on cancer invasiveness and progression in PTC may be explained by increased TERT expression, which may result from the BRAF-induced upregulation of several ETS transcription factors.
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Wang, Liye, Qianyi Lu, Kuikui Jiang, Ruoxi Hong, Shusen Wang, and Fei Xu. "BRAF V600E Mutation in Triple-Negative Breast Cancer: A Case Report and Literature Review." Oncology Research and Treatment 45, no. 1-2 (November 24, 2021): 54–61. http://dx.doi.org/10.1159/000520453.
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Background: The B-Raf proto-oncogene (BRAFV600E) gene mutation has been identified in a variety of malignancies, but no evidence of the efficacy of vemurafenib treatment in BRAFV600E mutant breast cancer (BC) has been reported. Case Presentation: We reported a 60-year-old woman with confirmed triple-negative BC with BRAFV600E mutation. Progression-free survival (PFS) for first-line chemotherapy was 7 months. The patient received vemurafenib and albumin-bound paclitaxel as second-line therapy, exhibiting regression of some pulmonary metastatic lesions with concomitant progression of other lesions, and achieved 4.4 months of PFS. Genetic testing of the progressed pulmonary lesion revealed the BRAFV600E mutation, and acquired new mutations and AR amplification. The patient ultimately died of multiple organ failure and achieved 12 months of overall survival. Conclusions: The BRAFV600E mutation may be a potential prognostic factor and therapeutic target for BC.
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Gąsior-Perczak, Danuta, Artur Kowalik, Agnieszka Walczyk, Monika Siołek, Krzysztof Gruszczyński, Iwona Pałyga, Estera Mikina, et al. "Coexisting Germline CHEK2 and Somatic BRAFV600E Mutations in Papillary Thyroid Cancer and Their Association with Clinicopathological Features and Disease Course." Cancers 11, no. 11 (November 7, 2019): 1744. http://dx.doi.org/10.3390/cancers11111744.
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BRAFV600E is the most common somatic mutation in papillary thyroid carcinoma (PTC) and the majority of evidence indicates that it is associated with an aggressive clinical course. Germline mutations of the CHEK2 gene impair the DNA damage repair process and increase the risk of PTC. Coexistence of both mutations is expected to be associated with poorer clinical course. We evaluated the prevalence of concomitant CHEK2 and BRAFV600E mutations and their associations with clinicopathological features, treatment response, and disease course in PTC patients. The study included 427 unselected PTC patients (377 women and 50 men) from one center. Relationships among clinicopathological features, mutation status, treatment response, and disease outcomes were assessed. Mean follow-up was 10 years. CHEK2 mutations were detected in 15.2% and BRAFV600E mutations in 64.2% patients. Neither mutation was present in 31.4% cases and both BRAFV600E and CHEK2 mutations coexisted in 10.8% patients. No significant differences in clinicopathological features, initial risk, treatment response, or disease outcome were detected among these patient groups. CHEK2 mutations were significantly associated with older age, while BRAFV600E was significantly associated with older age and extrathyroidal extension. The coexistence of both mutations was not associated with more aggressive clinicopathological features of PTC, poorer treatment response, or disease outcome.
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Nikiforovich, P. A., A. P. Polyakov, I. V. Sleptsov, N. S. Boyko, Yu A. Gronskaya, N. I. Timofeeva, and R. A. Chernikov. "Targeted therapy of anaplastic thyroid cancer." Head and Neck Tumors (HNT) 12, no. 4 (March 8, 2023): 33–38. http://dx.doi.org/10.17650/2222-1468-2022-12-4-33-38.
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Introduction. Anaplastic thyroid cancer (ATC) is a very rare malignant tumor of the thyroid comprising 1–2 % of all thyroid cancers. In this pathology, response rate for standard systemic therapy is less than 15 %, and long-term results remain unsatisfactory. Additionally, there are no data conclusively showing that cytotoxic chemotherapy improves survival or quality of life in patients with ATC.Aim. To improve the results of treatment of patients with ATC through evaluation of the effectiveness of targeted therapy in cases of BRAFV600E mutation.Materials and methods. The multicenter prospective study included 29 patients with ATC IVB–C, T4a–bN1a–bM0–1. The patients were divided into 2 groups. The Group 1 (control) included 15 patients with resectable / nonresectable, metastatic / nonmetastatic ATC (without BRAFV600E mutation), stages IVB–C who received standard types of treatment (surgical intervention, radiation, and chemotherapy). The Group 2 consisted of 14 patients with nonresectable or metastatic ATC, stages IVB–C, who received combination therapy (surgical intervention, radiation, and chemotherapy) with inclusion of inhibitors of BRAF dabrafenib and trametinib in neoadjuvant and adjuvant regimens.Results. The study showed the effectiveness of targeted therapy with inhibitors of BRAF mutations in treatment of locally advanced non-operable metastatic ATC with BRAFV600E mutation. Overall response (complete response + partial response) in the Group 1 was 0 %, in the Group 2 it was 64 %. Therefore, treatment scheme dabrafenib + trametinib is a prmising approach to combination targeted therapy in patients with ATC and BRAFV600E mutation. Conclusion. Dabrafenib + trametinib is a promising combination targeted therapy option for patients with ATC with a BRAFV600 mutation demonstrates a high overall response rate, a prolonged duration of response, and an increase in survival rates with controlled toxicity.
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Emile, Jean-François, Eli L. Diamond, Zofia Hélias-Rodzewicz, Fleur Cohen-Aubart, Frédéric Charlotte, David M. Hyman, Eunhee Kim, et al. "Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease." Blood 124, no. 19 (November 6, 2014): 3016–19. http://dx.doi.org/10.1182/blood-2014-04-570937.
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Key Points PIK3CA and NRAS mutations are recurrent in BRAFV600E wild-type ECD patients. 57.5% (46/80) of ECD patients have a BRAFV600E mutation, and an additional 10.9% and 3.7% have PIK3CA and NRAS mutations, respectively.
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Jin, Lei, Liang Zhou, Jian-Biao Wang, Li Tao, Xiao-Xiao Lu, Na Yan, Qian-Ming Chen, Li-Ping Cao, and Lei Xie. "Whether Detection of Gene Mutations Could Identify Low- or High-Risk Papillary Thyroid Microcarcinoma? Data from 393 Cases Using the Next-Generation Sequencing." International Journal of Endocrinology 2024 (January 16, 2024): 1–12. http://dx.doi.org/10.1155/2024/2470721.
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Objective. The objective of this study is to explore the utilization of next-generation sequencing (NGS) technology in evaluating the likelihood of identifying individuals with papillary thyroid microcarcinoma (PTMC ≤10 mm) who are at high or low risk. Design. NGS was used to analyze 393 formalin-fixed, paraffin-embedded tissues of PTC tumors, all of which were smaller than 15 mm. Results. The study found that bilateralism, multifocality, intrathyroidal spread, and extrathyroidal extension were present in 84 (21.4%), 153 (38.9%), 16 (4.1%), and 54 (13.7%) cases, respectively. Metastasis of cervical lymph nodes was identified in 226 (57.5%) cases and 96 (24.4%) cases with CLNM >5. Out of the total number of cases studied, 8 cases (2.3%) showed signs of tumor recurrence, all of which were localized and regional. Genetic alterations were detected in 342 cases (87.0%), with 336 cases revealing single mutations and 6 cases manifesting compound mutations. 332 cases (84.5%) had BRAFV600E mutation, 2 cases had KRASQ61K mutation, 2 cases had NRASQ61R mutation, 8 cases had RET/PTC1 rearrangement, 3 cases had RET/PTC3 rearrangement, and 1 case had TERT promoter mutation. Additionally, six individuals harbored concurrent mutations in two genes. These mutations were of various types and combinations: BRAFV600E and NRASQ61R (n = 2), BRAFV600E and RET/PTC3 (n = 2), BRAFV600E and RET/PTC1 (n = 1), and BRAFV600E and TERT promoter (n = 1). The subsequent analysis did not uncover a significant distinction in the incidence of gene mutation or fusion between the cN0 and cN1 patient cohorts. The presence of BRAFV600E mutation and CLNM incidence rates were found to be positively correlated with larger tumor size in PTMC. Our data showed that gene mutations did not appear to have much to do with high-risk papillary thyroid microcarcinoma (PTMC). However, when we looked at tumor size, we found that if the tumor was at least 5 millimeters in size, there was a higher chance of it being at high risk for PTM (P<0.001, odds ratio (OR) = 2.55, 95% confidence interval (CI): 1.57–4.14). Identification of BRAFV600E mutation was not demonstrated to be significantly correlated with advanced clinicopathological characteristics, although it was strongly associated with a bigger tumor diameter (OR = 4.92, 95% CI: 2.40–10.07, P<0.001). Conclusion. In clinical practice, BRAFV600E mutation does not consistently serve as an effective biomarker to distinguish high-risk PTMC or predict tumor progression. The size of the tumor has a significant correlation with its aggressive characteristics. PTMC with a diameter of ≤5 mm should be distinguished and targeted as a unique subset for specialized treatment.
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Sui, Jane Sze Yin, Marc Ladanyi, Charles M. Rudin, Alexander E. Drilon, Gregory J. Riely, Mark G. Kris, and Michael Offin. "Clinicopathologic and mutational landscape of BRAFV600E-mutant non–small cell lung carcinoma." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 9084. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.9084.
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9084 Background: BRAF mutations (mts) occur in 2-5% of non-small cell lung cancers (NSCLC) with approximately 50% being BRAFV600E. Limited data is known regarding the mutational landscape (ML) and prognostic role of co-mutations in BRAFV600E NSCLC. We performed this study to evaluate clinicopathological characteristics and the impact of ML in BRAFV600E NSCLC. Methods: Patients (pts) with BRAFV600Emutant NSCLC were identified using MSK-IMPACT at Memorial Sloan Kettering Cancer Center between January 2014 to October 2021. Baseline clinicopathological characteristics and treatment outcomes were annotated. Due to the enrichment of SETD2 in BRAFV600E NSCLC, we conducted further analyses using cbioportal to identify co-mutations of SETD2 with other actionable mutations in NSCLC. Overall survival (OS) was assessed from the date of metastatic disease until death using the log-rank test. Results: BRAF mutations were detected in 5% of NSCLC samples (512/10220) with 22% (97/435 pts) being BRAFV600E. Of the 97 pts with BRAFV600E NSCLC identified: 57 pts (59%) were females, median age of 68 (range: 38-93 years), 58 pts (60%) were former smokers. All BRAFV600E tumors were adenocarcinoma and the median tumor mutational burden was 5 mt/Mb (range: 0-40). 46 pts (48%) with BRAFV600E NSCLC were diagnosed with de novo metastatic disease. Pts receiving targeted therapy at first, second, and subsequent lines of therapy numbered 17 (29%), 18 (31%), and 10 (17%) respectively. Co-alterations of BRAFV600E with TP53 and SETD2 were found in 45% (44/97) and 42% (41/97), respectively. There is a much lower prevalence of concurrent inactivating SETD2 mutations than with other actionable alterations in NSCLC: ROS1 (9%), ALK (8%), RET (8%), HER2 (6%), MET (5%), KRAS (5%), EGFR (2.9%) and BRAFnon-V600E (2%). Median OS in BRAFV600E+/ TP53+ vs BRAFV600E+/ SETD2+ were 35 vs 36 mos (HR 0.88m 95% CI 0.45-1.75, P= 0.71) and BRAFV600E+/ TP53+/ SETD2+ vs BRAFV600E+/ TP53-/ SETD2- were 19 vs 39 mos (HR 0.37, 95% CI 0.09-1.50, P= 0.06). Conclusions: Among the BRAFV600E lung adenocarcinomas, concurrent TP53 mutation and SETD2 inactivation define a patient subset with significantly shorter overall survival. Further studies are warranted to investigate the role of SETD2 mutations in the context of BRAFV600E in NSCLC pts.
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Sui, Jane Sze Yin, Marc Ladanyi, Charles M. Rudin, Alexander E. Drilon, Gregory J. Riely, Mark G. Kris, and Michael Offin. "Clinicopathologic and mutational landscape of BRAFV600E-mutant non–small cell lung carcinoma." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 9084. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.9084.
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9084 Background: BRAF mutations (mts) occur in 2-5% of non-small cell lung cancers (NSCLC) with approximately 50% being BRAFV600E. Limited data is known regarding the mutational landscape (ML) and prognostic role of co-mutations in BRAFV600E NSCLC. We performed this study to evaluate clinicopathological characteristics and the impact of ML in BRAFV600E NSCLC. Methods: Patients (pts) with BRAFV600Emutant NSCLC were identified using MSK-IMPACT at Memorial Sloan Kettering Cancer Center between January 2014 to October 2021. Baseline clinicopathological characteristics and treatment outcomes were annotated. Due to the enrichment of SETD2 in BRAFV600E NSCLC, we conducted further analyses using cbioportal to identify co-mutations of SETD2 with other actionable mutations in NSCLC. Overall survival (OS) was assessed from the date of metastatic disease until death using the log-rank test. Results: BRAF mutations were detected in 5% of NSCLC samples (512/10220) with 22% (97/435 pts) being BRAFV600E. Of the 97 pts with BRAFV600E NSCLC identified: 57 pts (59%) were females, median age of 68 (range: 38-93 years), 58 pts (60%) were former smokers. All BRAFV600E tumors were adenocarcinoma and the median tumor mutational burden was 5 mt/Mb (range: 0-40). 46 pts (48%) with BRAFV600E NSCLC were diagnosed with de novo metastatic disease. Pts receiving targeted therapy at first, second, and subsequent lines of therapy numbered 17 (29%), 18 (31%), and 10 (17%) respectively. Co-alterations of BRAFV600E with TP53 and SETD2 were found in 45% (44/97) and 42% (41/97), respectively. There is a much lower prevalence of concurrent inactivating SETD2 mutations than with other actionable alterations in NSCLC: ROS1 (9%), ALK (8%), RET (8%), HER2 (6%), MET (5%), KRAS (5%), EGFR (2.9%) and BRAFnon-V600E (2%). Median OS in BRAFV600E+/ TP53+ vs BRAFV600E+/ SETD2+ were 35 vs 36 mos (HR 0.88m 95% CI 0.45-1.75, P= 0.71) and BRAFV600E+/ TP53+/ SETD2+ vs BRAFV600E+/ TP53-/ SETD2- were 19 vs 39 mos (HR 0.37, 95% CI 0.09-1.50, P= 0.06). Conclusions: Among the BRAFV600E lung adenocarcinomas, concurrent TP53 mutation and SETD2 inactivation define a patient subset with significantly shorter overall survival. Further studies are warranted to investigate the role of SETD2 mutations in the context of BRAFV600E in NSCLC pts.
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Liu, Shiyang, Bo Jiao, Shuyu Li, Lu Zhao, Weihong Zheng, Kun Wang, Jing Xu, et al. "Oestrogen receptor alpha in papillary thyroid carcinoma: association with clinical features and BRAFV600E mutation." Japanese Journal of Clinical Oncology 51, no. 7 (April 24, 2021): 1051–58. http://dx.doi.org/10.1093/jjco/hyab058.
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Abstract Background Papillary thyroid cancer cells can express oestrogen receptor alpha, which is encoded by the ESR1 gene and may bind to oestrogen to induce the occurrence and development of papillary thyroid cancer. The BRAFV600E mutation is also an important biomarker for the occurrence and progression of papillary thyroid cancer. However, the association between the BRAFV600E mutation and oestrogen receptor alpha expression has not been identified. This study aims to investigate the association between ESR1 expression and the BRAFV600E mutation and its clinical significance. Methods Oestrogen receptor alpha and BRAFV600E proteins were detected by immunohistochemical staining of formalin-fixed paraffin-embedded thyroid tissues from 1105 patients with papillary thyroid cancer at our institution. Messenger RNA expression counts of ESR1 and clinicopathologic information were obtained from The Cancer Genome Atlas database. Results Oestrogen receptor alpha protein expression was significantly associated with BRAFV600E protein. The positive rate of oestrogen receptor alpha protein in papillary thyroid cancer patients was significantly higher in males, younger patients and patients with the multifocal type. In papillary thyroid cancer patients with positive BRAFV600E protein, oestrogen receptor alpha expression was significantly correlated with central lymph node metastasis. Data from the The Cancer Genome Atlas database also suggested that the ESR1 messenger RNA level was associated with the BRAFV600E mutation. Furthermore, classification analysis performed according to a tree-based classification method demonstrated that higher ESR1 messenger RNA expression indicated poorer overall survival in papillary thyroid cancer patients with the BRAFV600E mutation. Conclusions The percentage of BRAFV600E mutations is increased in patients with higher ESR1 messenger RNA levels, and the BRAFV600E protein might be co-expressed with oestrogen receptor alpha, which could be an indicator of cervical lymph node metastasis and poor overall survival in patients with papillary thyroid cancer.
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Jouenne, Fanélie, Sylvie Chevret, Emmanuelle Bugnet, Emmanuelle Clappier, Gwenaël Lorillon, Véronique Meignin, Aurélie Sadoux, et al. "Genetic landscape of adult Langerhans cell histiocytosis with lung involvement." European Respiratory Journal 55, no. 2 (December 5, 2019): 1901190. http://dx.doi.org/10.1183/13993003.01190-2019.
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The clinical significance of the BRAFV600E mutation in adult Langerhans cell histiocytosis (LCH), including pulmonary Langerhans cell histiocytosis (PLCH), is not well understood. Similarly, the spectrum of molecular alterations involved in adult LCH has not been fully delineated. To address these issues, we genotyped a large number of adult LCH biopsies and searched for an association of identified molecular alterations with clinical presentation and disease outcome.Biopsies from 117 adult LCH patients, 83 with PLCH (median age 36.4 years, 56 females, 38 multisystem disease, 79 single system disease, 65 current smokers) were genotyped for the BRAFV600E mutation. In 69 cases, LCH lesions were also genotyped by whole-exome sequencing (WES) or targeted gene panel next-generation sequencing (NGS). Cox models were used to estimate the association of baseline characteristics with the hazard of LCH progression.MAPK pathway alterations were detected in 59 out of 69 cases (86%) (BRAFV600E mutation: 36%, BRAFN486_P490 deletion: 28%, MAP2K1 mutations: 15%, isolated NRASQ61 mutations: 4%), while KRAS mutations were virtually absent in PLCH lesions. The BRAFV600E mutation was not associated with LCH presentation at diagnosis, including smoking status and lung function, in PLCH patients. BRAFV600E status did not influence the risk of LCH progression over time.Thus, MAPK alterations are present in most lesions from adult LCH patients, particularly in PLCH. Unlike reports in paediatric LCH, BRAFV600E genotyping did not provide additional information on disease outcome. The search for alterations involved in the MAPK pathway, including BRAF deletions, is useful for guiding targeted treatment in selected patients with refractory progressive LCH.
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Dong, Si-Yang, Jie Chen, Er-Jie Xia, Ri-Xu Lin, Hai-Yan Du, Ou-Chen Wang, Xiao-Hua Zhang, and Ru-Tian Hao. "Clinical Analysis of BRAFV600E Mutation and Its Correlation With Sonographic Image Characteristics in Papillary Thyroid Carcinoma in Chinese Coastal Areas." American Surgeon 86, no. 5 (May 2020): 450–57. http://dx.doi.org/10.1177/0003134820919734.
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This study analyzed the characteristics of BRAFV600E mutation in papillary thyroid carcinoma (PTC) in Chinese coastal areas. We intended to identify noninvasive methods to determine BRAFV600E status in thyroid nodules prior to surgery. BRAFV600E mutation and the sonographic characteristics of thyroid nodules were investigated in 670 PTC patients in our hospital. We aimed to determine the relationship between BRAFV600E mutation and the clinicopathological and sonographic imaging characteristics of PTC. The mutation rate of the BRAFV600E was 78.2%. BRAFV600E mutation was significantly associated with central node (univariate analyses, P = .005; multivariate analyses, P < .001, odds ratio [OR] = 10.255) and lateral node metastases (univariate analyses, P = .001; multivariate analyses, P < .001, OR = 22). It was less frequent in PTC coexisting with Hashimoto’s thyroiditis (univariate analyses, P = .016; multivariate analyses, P < .001, OR = .034). Nodules without blood flow had a significantly higher mutation rate of BRAFV600E in PTC patients (univariate analyses, P = .026). BRAFV600E mutation was significantly associated with high suspicion in the Thyroid Imaging Reporting and Data System 5 (univariate analyses, P = .004; multivariate analyses, P = .014, OR = 6.456). Our results strongly suggest that BRAFV600E mutation plays a potential role in lymph node metastasis (central node metastasis, OR = 10.225; lateral node metastasis, OR = 22). Some sonographic imaging features might be helpful in estimating the status of BRAFV600E preoperatively.
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Elisei, Rossella, Clara Ugolini, David Viola, Cristiana Lupi, Agnese Biagini, Riccardo Giannini, Cristina Romei, Paolo Miccoli, Aldo Pinchera, and Fulvio Basolo. "BRAFV600E Mutation and Outcome of Patients with Papillary Thyroid Carcinoma: A 15-Year Median Follow-Up Study." Journal of Clinical Endocrinology & Metabolism 93, no. 10 (October 1, 2008): 3943–49. http://dx.doi.org/10.1210/jc.2008-0607.
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Background: The BRAFV600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). The role of BRAFV600E mutation as a poor prognostic factor has been controversially reported in series with short-term follow-ups. In this study we verified the prognostic value of the BRAFV600E mutation in PTC patients with a long-term follow-up. Methods: We studied 102 PTC patients with a median follow-up of 15 yr. The BRAFV600E mutation was analyzed by PCR-single-strand conformational polymorphism and sequencing. The correlation between the presence/absence of the BRAFV600E mutation, clinicopathological features, and outcome of PTC patients were evaluated. Results: The BRAFV600E mutation was found in 38 of 102 (37.3%) PTC patients, and was significantly more frequent in patients older than 60 yr (P = 0.02), in advanced stages (P = 0.03), and in cases with vascular invasion (P = 0.02). At univariate analysis the worst outcome for PTC patients was significantly correlated with clinicopathological features (i.e. age, tumor size, extrathyroid extension, lymph node and distant metastases, advanced stage, vascular endothelial growth factor expression, and vascular invasion) and the BRAFV600E mutation (P < 0.002). However, at multivariate analysis only the BRAFV600E mutation showed an independent correlation with the worst outcome (P = 0.03). Moreover, the survival curves of PTC patients showed a lower percentage of survivors in the BRAFV600E-mutated group (P = 0.015). Conclusions: In this study the BRAFV600E mutation correlated with the worst outcome for PTC patients, who were not only at a higher risk not to be cured but also for death. In particular, the BRAFV600E mutation was demonstrated to be a poor prognostic factor independent from other clinicopathological features.
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Yamazaki, Kentaro, Takayuki Yoshino, Katsuya Tsuchihara, Eiji Shinozaki, Kei Muro, Tomohiro Nishina, Kensei Yamaguchi, et al. "Clinical impact of expanded BRAF mutational status on the outcome for metastatic colorectal cancer patients with anti-EGFR antibody: An analysis of the BREAC trial (Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics)." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 573. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.573.
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573 Background: BRAFV600E mutation has been recognized as a prognostic marker in patients (pts) with metastatic colorectal cancer (mCRC). Several studies have consistently shown a significant association between the presence of BRAFV600E mutation and resistance to anti-EGFR antibody therapy in pts with previously treated mCRC while there are few reports on the clinical impact of minor BRAF mutations. Methods: The BREAC trial was a multicenter, retrospective study to investigate the novel biomarkers of anti-EGFR antibody therapy. RAS and BRAF mutations were detected by targeted sequencing using FFPE materials of mCRC pts who received anti-EGFR antibody after a failure to standard therapies. Progression-free survival (PFS), overall survival (OS), and response rate (RR) were evaluated according to expanded RAS/BRAF mutational status. Results: Of 184 pts enrolled in the study, RAS/BRAF testing was succeeded in 150 pts. Patients characteristics were as follows; male/female 87/63, median age 63.5 years (range, 28-85), PS 0/1/2 81/65/4. Median PFS, OS, and RR were 4.0 months, 12.4 months, and 21%, respectively. Expanded RAS and BRAF mutations were detected in 40 pts (26.7%, KRAS/NRAS 29/11) and in 16 pts (10.7%, BRAFV600E/other 9/7), respectively. Observed BRAF mutations other than BRAFV600E were located at kinase domain. The clinical outcomes of other BRAF mutations were worse similar to those of BRAFV600E and expanded RAS mutations (Table). Conclusions: Expanded BRAF mutations might predict a lack of response for mCRC pts who received anti-EGFR antibody. Further investigation is warranted to confirm the clinical impact of expanded BRAF mutations. [Table: see text]
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Soria, Xavier, Felip Vilardell, Óscar Maiques, Carla Barceló, Pol Sisó, Inés de la Rosa, Ana Velasco, et al. "BRAFV600E Mutant Allele Frequency (MAF) Influences Melanoma Clinicopathologic Characteristics." Cancers 13, no. 20 (October 11, 2021): 5073. http://dx.doi.org/10.3390/cancers13205073.
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Background: Cutaneous melanoma shows high variability regarding clinicopathological presentation, evolution and prognosis. Methods: Next generation sequencing was performed to analyze hotspot mutations in different areas of primary melanomas (MMp) and their paired metastases. Clinicopathological features were evaluated depending on the degree of variation of the BRAFV600E mutant allele frequency (MAF) in MMp. Results: In our cohort of 14 superficial spreading, 10 nodular melanomas and 52 metastases, 17/24 (71%) melanomas had a BRAFV600E mutation and 5/24 (21%) had a NRASQ61 mutation. We observed a high variation of BRAFV600E MAF (H-BRAFV600E) in 7/17 (41%) MMp. The H-BRAFV600E MMp were all located on the trunk, had lower Breslow and mitotic indexes and predominantly, a first nodal metastasis. Regions with spindled tumor cells (Spin) and high lymphocytic infiltrate (HInf) were more frequent in the H-BRAFV600E patients (4/7; 57%), whereas regions with epithelial tumor cells (Epit) and low lymphocytic infiltrate (LInf) were predominant (6/10; 60%) and exclusive in the low BRAFV600E MAF variation tumors (L-BRAFV600E). The H-BRAFV600E/Spin/HInf MMp patients had better prognostic features and nodal first metastasis. Conclusions: The H-BRAFV600E MMp were located on the trunk, had better prognostic characteristics, such as lower Breslow and mitotic indexes as well as high lymphocytic infiltrate.
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Attia, Abdallah S., Mohammad Hussein, Peter P. Issa, Ahmad Elnahla, Ashraf Farhoud, Brandon M. Magazine, Mohanad R. Youssef, et al. "Association of BRAFV600E Mutation with the Aggressive Behavior of Papillary Thyroid Microcarcinoma: A Meta-Analysis of 33 Studies." International Journal of Molecular Sciences 23, no. 24 (December 9, 2022): 15626. http://dx.doi.org/10.3390/ijms232415626.
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An association between the BRAFV600E mutation and the clinicopathological progression of papillary thyroid microcarcinoma (PTMC) has been suggested. We aimed to summarize the relevant literature and determine the predictive value of BRAFV600E mutation in predicting clinical outcomes and risk stratification in patients with PTMC. A systematic search using PubMed, Cochrane, and Embase up to February 2020 was performed. A total of 33 studies met the inclusion criteria, resulting in a pool of 8838 patients, of whom 5043 (57.1%) patients were positive for BRAFV600E mutation. Tumors with positive BRAFV600E mutation had a higher tendency for multifocality (RR = 1.09, 95%CI = 1.03–1.16), extrathyroidal extension (RR = 1.79, 95%CI = 1.37–2.32), and lymph node metastasis (RR = 1.43, 95%CI = 1.19–1.71). Patients with BRAFV600E mutation were at increased risk of disease recurrence (RR = 1.90, 95%CI = 1.43–2.53). PTMC in patients positive for the BRAFV600E mutation is more aggressive than wild-type BRAF PTMC. Since BRAF-mutated PTMC is generally more resistant to radioiodine treatment, patients with BRAFV600E-mutated PTMC may require earlier management, such as a minimally invasive ablative intervention. Conservative management by active surveillance may be suitable for patients with wild-type BRAFV600E PTMC.
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Hong, Xiaoquan, Juxiang Li, Shaoyin Duan, and Youkuang You. "Retrospective study of BRAFV600E mutation and CT features of papillary thyroid carcinoma." PeerJ 12 (January 24, 2024): e16810. http://dx.doi.org/10.7717/peerj.16810.
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Objective This study aimed to examine the correlation between BRAFV600E status and computed tomography (CT) imaging characteristics in papillary thyroid carcinoma (PTC) and determine if suspicious CT imaging features could predict BRAFV600E status. Methods This retrospective study included patients with pathologically confirmed PTC at the Department of Thyroid Surgery of Zhongshan Hospital, Xiamen University, between July 2020 and June 2022. We compared the clinicopathologic factors and CT findings of nodules with and without the mutation, and the multiple logistical regression test was used to determine independent parameters of the BRAFV600E mutation. Results This study included 381 patients with PTC, among them, BRAFV600E mutation was detected in 314 patients (82.4%). Multivariate logistic regression analysis showed that gender (OR = 0.542, 95% CI [0.296–0.993], P = 0.047) and shape (OR = 0.510, 95% CI [0.275–0.944], P = 0.032) were associated with BRAFV600E mutation. Conclusions Compared to BRAFV600E mutation-negative, BRAFV600E-positive PTC lesions were more likely to be found in female patients and were characterized by irregular shape. However, the CT imaging finding is not enough to predict BRAFV600E status, but an indication.
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JING, Fan-jing, Jun LIANG, Zhi-yong LIANG, Chao MENG, Wen LONG, Xiao-yi LI, and Yan-song LIN. "BRAFV600E mutation is not a positive predictor for distant metastasis in sporadic papillary thyroid carcinoma." Chinese Medical Journal 126, no. 16 (August 30, 2013): 3013–18. http://dx.doi.org/10.3760/cma.j.issn.0366-6999.20122032.
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Background BRAFV600E mutation is correlated with local aggressive clinicopathological features in papillary thyroid carcinoma; yet the relationship between this genetic variation and distant papillary thyroid carcinoma metastasis was unclear. This study aimed to investigate whether BRAFV600E is predictive for distant metastasis in the Chinese population. Methods One hundred and seven patients with papillary thyroid carcinoma were enrolled in this study, including 43 patients with distant metastasis and 64 patients without. Quantitative real-time polymerase chain reaction was used to detect BRAFV600E mutation, while immunohistochemistry was performed to detect vascular endothelial growth factor (VEGF) expression. The associations between distant metastasis and BRAFV600E mutation, and VEGF expression as well as local clinicopathological factors were determined. Results A total of 28.6% of the patients in the distant metastasis group harbored BRAFV600E mutation, which was significantly lower than in the without distant metastasis group (68.8%, P <0.001). BRAFV600E mutation was negatively correlated with positive VEGF expression (P=0.001). Furthermore, 52.2% of the patients with distant metastasis exhibited VEGF expression, compared with 25.0% of those without. Higher levels of VEGF expression were also observed in the distant metastasis group. Tumor size, extra-thyroid invasion, and BRAFV600E mutation were independent predictors for distant metastasis according to multivariate analysis (odds ratios were 2.8, 12.4, and 0.3; 95% CI 1.483-5.334, and 2.950-52.407, 0.100-0.890; P=0.002, 0.001, and 0.030, respectively). BRAFV600E mutation was negatively correlated with distant metastasis in adult subgroup analysis (P=0.005) but was not an independent parameter. Conclusions BRAFV600E mutation is predictive for distant metastasis in papillary thyroid carcinoma but not positively. VEGF may be involved in the pathogenesis of distant metastasis.
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Li, Fei, Guangqi Chen, Chunjun Sheng, Aaron M. Gusdon, Yueye Huang, Zhongwei Lv, Huixiong Xu, Mingzhao Xing, and Shen Qu. "BRAFV600E mutation in papillary thyroid microcarcinoma: a meta-analysis." Endocrine-Related Cancer 22, no. 2 (January 15, 2015): 159–68. http://dx.doi.org/10.1530/erc-14-0531.
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The prognostic value of the BRAFV600E mutation, resulting in poor clinical outcomes of papillary thyroid carcinoma, has been generally confirmed. However, the association of BRAFV600E with aggressive clinical behaviors of papillary thyroid microcarcinoma (PTMC) has not been firmly established in individual studies. We performed this meta-analysis to examine the relationship between BRAFV600E mutation and the clinicopathological features of PTMC. We conducted a systematic search in PubMed, EMBASE, and the Cochrane library for relevant studies. We selected all the studies that reported clinicopathological features of PTMC patients with information available on BRAFV600E mutation status. Nineteen studies involving a total of 3437 patients met these selection criteria and were included in the analyses. The average prevalence of the BRAFV600E mutation was 47.48%, with no significant difference with respect to patient sex (male versus female) and age (younger than 45 years versus 45 years or older). Compared with the WT BRAF gene, the BRAFV600E mutation was associated with tumor multifocality (odds ratio (OR) 1.38; 95% CI, 1.04–1.82), extrathyroidal extension (OR 3.09; 95% CI, 2.24–4.26), lymph node metastases (OR 2.43; 95% CI, 1.28–4.60), and advanced stage (OR 2.39; 95% CI, 1.38–4.15) of PTMC. Thus, our findings from this large meta-analysis definitively demonstrate that BRAFV600E-mutation-positive PTMC are more likely to manifest with aggressive clinicopathological characteristics. In appropriate clinical settings, testing for the BRAFV600E mutation is likely to be useful in assisting the risk stratification and management of PTMC.
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Otieno, Steve Biko, Syed Nasir, Alva Weir, and Robert Johnson. "Rapid Response in a Patient with Relapsed/Refractory Multiple Myeloma Treated with BRAF/MEK Inhibitors." Case Reports in Hematology 2020 (December 11, 2020): 1–4. http://dx.doi.org/10.1155/2020/8821415.
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Patients with relapsed and refractory multiple myeloma have a poor prognosis. The mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathogenesis of multiple myeloma. Several mutations in this pathway can lead to its constitutive activation leading to oncogenesis. One such mutation is BRAFV600E which is a therapeutic target in the treatment of melanoma, lung cancer, colon cancer, thyroid cancer, and hairy cell leukemia. BRAFV600E-directed therapy currently does not have approval in multiple myeloma. It has been proposed that this mutation leads to proteasome inhibitor resistance. About 4–10% of multiple myeloma cases harbor the BRAFV600E mutation. Herein, we report a case of a patient with relapsed and refractory multiple myeloma who had a progression-free survival (PFS) of 8.5 months on BRAF-targeted therapy.
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Kim, Suk Kyeong, Tae Sook Hwang, Young Bum Yoo, Hye Seung Han, Dong-Lim Kim, Kee-Ho Song, So Duk Lim, Wan Seop Kim, and Nam Sun Paik. "Surgical Results of Thyroid Nodules according to a Management Guideline Based on the BRAFV600E Mutation Status." Journal of Clinical Endocrinology & Metabolism 96, no. 3 (March 1, 2011): 658–64. http://dx.doi.org/10.1210/jc.2010-1082.
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Context: In Korea, where PTC comprises about 90–95% of the reported thyroid cancers, the prevalence of BRAFV600E mutation in papillary thyroid carcinoma (PTC) is above 80%. Objective: We analyzed the surgical result according to a management guideline based on the BRAFV600E mutation status of thyroid nodules. Design: A total of 865 thyroid nodules were prospectively analyzed for their cytology and BRAFV600E mutation status by pyrosequencing. For the patients who had a diagnosis of atypical cells of undetermined significance (ACUS), we recommended surgery when there was positivity for BRAFV600E mutation or the nodules were clinically suspicious. Results: Among 865 cases, 504, 141, 54, 140, 10, and 16 were diagnosed as benign, ACUS, suspicious for malignancy, malignant, suspicious for follicular neoplasm, and nondiagnostic, respectively. None of the 504 benign, 45 (31.9%) of the 141 ACUS, 46 (85.2%) of the 54 suspicious for malignancy, 129 (92.1%) of the 140 malignant, and one (10%) of the 10 suspicious for follicular neoplasm cases showed BRAFV600E mutation. Surgery was recommended to all 45 patients with BRAFV600E mutation-positive ACUS nodules; among them, 30 patients underwent surgery, 29 had PTC, and one had nodular hyperplasia. All the patients diagnosed as suspicious for malignancy or malignant were advised to undergo an operation, and they turned out to have PTCs regardless of their BRAFV600E mutation status. Conclusions: We found that performing BRAFV600E mutation analysis on the fine-needle aspiration biopsy specimens was of great help to make a therapeutic decision for thyroid nodules when the fine-needle aspiration biopsy results were equivocal.
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Wei, Xiaojing, Xiaodong Wang, Jie Xiong, Chen Li, Yixuan Liao, Yongjun Zhu, and Jingxin Mao. "Risk and Prognostic Factors for BRAFV600E Mutations in Papillary Thyroid Carcinoma." BioMed Research International 2022 (May 18, 2022): 1–13. http://dx.doi.org/10.1155/2022/9959649.
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Background. Over the past ten years, the incidence rate of papillary thyroid carcinoma (PTC) worldwide has been increasing rapidly year by year, with the incidence rate increasing 6% annually. PTC has become the malignant tumor with the highest growth rate in the world that fourteen PTC-related mutant genes have been identified. Whether the BRAFV600E mutation related to more aggressive clinicopathologic features and worse outcome in PTC remains variable and controversial. We aim to investigate the risk factors that may predict the BRAFV600E mutation potential of these lesions and new prevention strategies in PTC patients. Methods. A total of 9,908 papillary thyroid carcinoma patients with average 74.6% BRAFV600E mutations were analyzed (RevMan 5.3 software) in this study. The PubMed, Embase, and ISI Web of Science databases were systematically searched for works published through December 15, 2021. Results. The following variables were associated with an increased risk of BRAFV600E mutation in PTC patients: age ≥ 45 years ( OR = 1.39 , 95 % CI = 1.21 – 1.60 , p < 0.00001 ), male gender ( OR = 1.13 , 95 % CI = 0.99 – 1.28 , p = 0.06 ), multifocality ( OR = 1.22 , 95 % CI = 1.07 – 1.40 , p = 0.004 ), lymph node metastasis ( OR = 1.33 , 95 % CI = 0.79 – 2.23 , p = 0.28 ), extrathyroidal extension + ( OR = 1.61 , 95 % CI = 1.06 – 2.44 , p = 0.03 ), vascular invasion + ( OR = 2.04 , 95 % CI = 1.32 – 3.15 , p = 0.001 ), and tumor node metastasis stage ( OR = 1.61 , 95 % CI = 1.38 – 1.88 , p < 0.00001 ). In addition, tumor size (>1 cm) ( OR = 0.51 , 95 % CI = 0.32 – 0.81 , p = 0.005 ) and distant metastasis ( OR = 0.69 , 95 % CI = 0.22 – 2.21 , p = 0.54 ) had no association or risk with BRAFV600E mutation in PTC patients. Conclusion. Our systematic review identified the following significant risk factors of BRAFV600E mutation in PTC patients: age (≥45 years), gender (male), multifocality, lymph node metastasis, vascular invasion, extrathyroidal extension, and advanced tumor node metastasis stage (stages III and IV). Tumor size (>1 cm) and distant metastasis do not appear to be correlated with BRAFV600E mutation in PTC patients.
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Colle, Raphael, Sara Lonardi, Marine Cachanado, Michael J. Overman, Elena Elez, Marwan Fakih, Francesca Corti, et al. "Impact of Lynch syndrome, BRAFV600E, and RAS mutations on outcomes in MSI/dMMR metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI): Analysis of combined international cohorts." Journal of Clinical Oncology 41, no. 4_suppl (February 1, 2023): 171. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.171.
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171 Background: ICI have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC . Lynch (LS) vs sporadic (Sp) status, BRAFV600E and RAS mutations (mt) are known factors of clinical and molecular heterogeneity in this population. We aimed to evaluate the prognostic value of these parameters in ICI-treated MSI mCRC pts. Methods: Pts are drawn from international cohorts (France, Italy, Spain, and USA). Pts were considered to have cancer linked to LS only in case of determined germline mutation and Sp in case of loss of MLH1/PMS2 protein expression associated with BRAF V600E mutation and/or hypermethylation of MLH1 promoter, or in case of biallelic somatic mutations of MMR genes. Survival analyses: progression-free survival (PFS) per iRECIST criteria and overall survival (OS) were adjusted on prognostic modifiers, selected on unadjusted analysis (p < 0.2) in case of limited number of events. Results: On the 466 pts included, 112 (24%) received ICI in first line, 305 (65%) received anti-PD1 alone, 161 (35%) anti-PD1 plus anti-CTLA4, 129 (29%) had BRAFV600Emt and 153 (34%) RASmt. Median follow-up was 24.0 months. In adjusted analysis of the whole population (n=466; 186 PFS events and 143 OS events), no association with PFS and OS was observed for BRAFV600E mt (PFS HR 1.20 [0.80 to 1.79], p=0.372; OS HR 1.06 [0.66 to 1.70], p= 0.811) and RASmt (PFS HR 0.93 [0.64 to 1.36], p= 0.712; OS HR 0.75 [0.48 to 1.17] p= 0.202). Adjusting factors were age, ECOG status, number of prior chemotherapies, treatment type (bi vs monotherapy), sidness (right vs left + rectum), primary tumor surgery. Concerning the population with determined Lynch status (n= 242; 83 PFS events and 54 OS events), PFS results are displayed. The analysis of impact of LS was not adjusted on BRAFV600E mutational status due to collinearity. In adjusted analysis, LS improved PFS compared with Sp (HR = 0.49, 95%CI (0.25 to 0.96), p = 0.036). Adjusted HR for OS was 0.56 without reaching significance 95%CI (0.25 to 1.22), p = 0.143. Conclusions: In this analysis of ICI-treated MSI/dMMR mCRC pts, RAS/BRAFV600E mutations are not associated with survival while Lynch syndrome pts demonstrated improved PFS. [Table: see text]
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Nechifor-Boilă, Adela, Ancuţa Zahan, Claudia Bănescu, Valeriu Moldovan, Doina Piciu, Septimiu Voidăzan, and Angela Borda. "Impact of BRAFV600E Mutation on Event-Free Survival in Patients with Papillary Thyroid Carcinoma: A Retrospective Study in a Romanian Population." Cancers 15, no. 16 (August 11, 2023): 4053. http://dx.doi.org/10.3390/cancers15164053.
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We aimed to evaluate the prognostic value of BRAFV600E mutation in a series of 127 papillary thyroid carcinoma (PTC) cases as a single factor, and in synergic interaction with other standard risk factors. BRAFV600E mutation was assessed by real-time PCR. Event-free survival (EFS) was calculated between the date of the first evaluation and the date of occurrence of an adverse event or the date of the last known status. The prevalence of BRAFV600E mutation was 57.2%. The Kaplan–Meier analysis showed a significant reduction of EFS among cases harboring BRAFV600E mutation compared to non-mutated cases (p = 0.010). In addition, BRAFV600E mutation was found to better predict adverse outcomes when associated with the following risk factors: age ≥ 55 years old (p < 0.001), male gender (p < 0.001), conventional (p = 0.005) and tall cell (p = 0.014) histology, tumor size > 40 mm (p = 0.001), extrathyroidal extension (p = 0.001), multifocality (p = 0.001) and lymph node metastasis (p < 0.001). In univariate analysis, a 3.74-fold increased risk for a reduced EFS (p = 0.018) was found for BRAFV600E-mutated cases, but no increased risk was further confirmed by multivariate analysis. Our results highlight that BRAFV600E mutation cannot be used alone as an independent predictive factor in PTC patients, but is prognostically valuable if integrated in the context of other clinicopathological risk factors.
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Hyman, David M., Eli Diamond, Cecile Rose Vibat, Latifa Hassaine, Jason Poole, Minal Patel, Veronica Holley, et al. "Prospective Blinded Study of BRAFV600E Mutation Detection in Cell-Free DNA of Patients with Systemic Histiocytic Disorders." Blood 124, no. 21 (December 6, 2014): 1833. http://dx.doi.org/10.1182/blood.v124.21.1833.1833.
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Abstract Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD) are systemic histiocytic disorders characterized by infiltration of histiocytes in multiple tissues of the body leading to organ compromise. Although the underlying etiology of these conditions has long been enigmatic, recent investigations have determined that LCH and ECD are clonal disorders of myeloid-derived precursor cells with a high frequency of BRAFV600E mutations (40-60% of patients). Moreover, treatment of BRAF-mutant LCH and ECD patients with the BRAF inhibitor vemurafenib has demonstrated dramatic efficacy. The above data underline the importance of accurately identifying BRAF mutational status in patients with systemic LCH and ECD. Unfortunately, the scant histiocyte content and marked stromal contamination, which are a hallmark of these disorders, make mutation detection in tissue biopsies challenging. Moreover,the propensity of histiocytic lesions to involve difficult to biopsy locations frequently necessitates the use of bone biopsies further limiting the availability of suitable tumor material for BRAF genotyping. We therefore initiated a prospective, blinded, multicenter study of BRAFV600E mutation detection in the cell-free DNA (cfDNA) from plasma and urine of histiocytosis patients to determine the sensitivity/specificity of cfDNA mutation detection compared with tissue biopsy and to track disease burden serially with therapy. Between January 2013 and June 2014, 30 consecutive patients with ECD (n=25) and LCH (n=5) were enrolled from Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center. Initial BRAF tissue mutation testing on tissue biopsies was performed by a variety of methods as part of routine care in CLIA-certified molecular diagnostic laboratories. We applied a droplet-digitial PCR assay (RainDrop ddPCR) for quantitative detection of the BRAFV600E mutation in plasma and urine cell-free cfDNA in all patients. Of 30 patients enrolled, initial tissue BRAFV600E genotyping identified 15 patients to be mutant, 6 patients as wildtype, and 9 as indeterminate. There was 100% concordance between tissue and urinary cfDNA genotype in samples from treatment naïve patients (sensitivity 92.9%, specificity 100%, positive predictive value 100%, negative predictive value 85.7% compared to tissue biopsy detection). Urinary cfDNA analysis identified 5 patients as being BRAFV600E mutant that were not known to have the BRAF mutation previously (Figure A). Subsequent tissue biopsy was performed in 2 of these patients and identified the BRAFV600E mutation, allowing both patients to enroll in an ongoing phase II study of vemurafenib. Results from plasma cfDNA for identifying the BRAFV600E mutation were comparable to urinary cfDNA results Next examining serial samples during therapy, a significant decrease in the cfDNA BRAFV600E:BRAF wildtype ratio was seen with therapy compared with pretreatment samples (p<0.0001). In all 10 patients treated with a BRAF inhibitor, serial urinary cfDNA analysis revealed progressive decrements in the BRAFV600E allele burden. Weekly serial urinary cfDNA analysis throughout the course of BRAF inhibitor therapy revealed that the decline in mutant cfDNA burden in response to BRAF inhibitors was consistent with radiographic disease improvement (Figure B). Moreover, in at least one patient where successful RAF inhibitor therapy was discontinued for toxicity, urinary cfDNA BRAFV600E burden increased after vemurafenib discontinuation which mirrored radiographic evidence of disease recurrence. Finally, 2 patients treated with the IL1-receptor antagonist anakinra exhibited substantial decreases in BRAFV600E burden, highlighting an effect of IL-1 receptor antagonism in BRAF-mutant histiocytes. These results indicate that cfDNA BRAFV600E mutational analysis in plasma and urine provides a convenient and reliable method of detecting mutational status and can serve as a non-invasive biomarker to monitor response to therapy in LCH and ECD. Moreover, the dynamic results achieved with cfDNA analysis allowed for monitoring of disease recurrence with treatment cessation. Of note, this study represents the largest prospective study of adult ECD patients to date. Moreover, these data represent the first evidence of the effect of RAF inhibition as well as IL1-receptor antagonism on the BRAF mutant clone in patients with histiocytosis. Figure 1 Figure 1. Disclosures Vibat: Trovagene Inc.: Employment. Hassaine:Trovagene Inc.: Employment. Poole:Trovagene Inc.: Employment. Lu:Trovagene Inc.: Employment. Erlander:Trovagene Inc.: Employment. Janku:Trovagene Inc.: Consultancy, Research Funding.
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Vignali, Paola, Elisabetta Macerola, Anello Marcello Poma, Rebecca Sparavelli, and Fulvio Basolo. "Indeterminate Thyroid Nodules: From Cytology to Molecular Testing." Diagnostics 13, no. 18 (September 20, 2023): 3008. http://dx.doi.org/10.3390/diagnostics13183008.
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Thyroid cancer is the most common malignancy of the endocrine system. Fine-needle aspiration (FNA) biopsy of thyroid nodules has become the gold standard procedure, in terms of cost and efficacy, for guiding clinicians towards appropriate patients’ management. One challenge for cytopathologists is to accurately classify cytological specimens as benign or malignant based on cytomorphological features. In fact, with a frequency ranging from 10% to 30%, nodules are diagnosed as indeterminate. In recent years, the mutational landscape of thyroid tumors has been extensively described, and two molecular profiles have been identified: RAS-like (NRAS, HRAS, and KRAS mutations; EIF1AX mutations; BRAF K601E mutation; and PPARG and THADA fusions) and BRAFV600E-like (including BRAFV600E mutation and RET and BRAF fusions). The purpose of this review is to discuss the latest molecular findings in the context of indeterminate thyroid nodules, highlighting the role of molecular tests in patients’ management.
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Zhu, Guoquan, Yuying Deng, Liqin Pan, Wei Ouyang, Huijuan Feng, Juqing Wu, Pan Chen, Jing Wang, Yanying Chen, and Jiaxin Luo. "Clinical significance of the BRAFV600E mutation in PTC and its effect on radioiodine therapy." Endocrine Connections 8, no. 6 (June 2019): 754–63. http://dx.doi.org/10.1530/ec-19-0045.
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The goal of this study was to explore the relationship of the BRAFV600E mutation with clinicopathologic factors and evaluate the effect of radioactive iodine (RAI) therapy in a large group of intermediate- and high-risk papillary thyroid cancer (PTC) patients with the BRAFV600E mutation and without distant metastases. We collected data for PTC patients who underwent total or near-total thyroidectomy and RAI treatment in our hospital from January 2014–December 2017. There were 1220 PTC patients who met the criteria, and the BRAFV600E mutation was observed in 979 of them (80.2%). Multivariate analysis identified that the BRAFV600E mutation remained independently associated with age at diagnosis, and bilaterality (OR = 1.023, 95% CI = 1.012–1.039, P < 0.001; OR = 1.685, 95% CI = 1.213–2.341, P = 0.002, respectively). In addition, the patients with bilateral PTCs had a higher prevalence of extrathyroid invasion, capsular invasion and fusion of metastatic lymph nodes than the unilateral PTC patients. The response to RAI therapy was evaluated in both the entire series and the patients with a high recurrence risk; no significant difference was discerned between the BRAFV600E mutation and the wild-type groups (P = 0.237 and P = 0.498, respectively). To summarize, our results confirmed that PTC patients with the BRAFV600E mutation exhibit more aggressive characteristics. In addition, the patients with bilateral PTC have a higher incidence of extrathyroid invasion. Moreover, BRAFV600E mutation PTC patients did not show a poorer clinical response after postsurgical RAI therapy, suggesting that RAI therapy may improve the general clinical outcome of these patients.
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M S, Bhuvitha, and Krishna G. "BRAFV600E Mutation in Papillary Carcinoma Thyroid." Annals of Pathology and Laboratory Medicine 9, no. 6 (July 9, 2022): A102–108. http://dx.doi.org/10.21276/apalm.3167.
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Background: Thyroid malignancies comprise 1 % of total human malignancies, Papillary Thyroid Carcinoma (PTC) is the most common malignant tumour of thyroid cancers. It is estimated that 80 % of thyroid malignancies are comprised of papillary carcinoma thyroid, which shows increased incidence in women. The most important etiology of PTC is mutation of RET/RAS/BRAF which activates MAPK signaling pathway. The BRAF V600E activating point mutation appears to be highly specific for PTC.
Methods: It is cross sectional study of 56 cases studied in the Government Medical college, Thiruvananthapuram, Kerala. Consecutive cases of histo-pathologically proven cases were selected and Immunohistochemical (IHC) studies for BRAFV600E were conducted, and results were recorded.
Result: Our study showed female preponderance and equal distribution of cases above and below 45 years of age. Size of the primary tumour was more than 1cm for majority of cases. In our study out of 56 cases studied 45 patients showed BRAFV600E expression comprising of 80% positivity. A 44% of the total cases studied showed lymph node metastasis.
Conclusion: We conclude in our study that BRAFV600E mutation is most common mutation in primary PTC patients. BRAFV600E expression most seen in elderly patients and shows strong association with lymph node metastasis. IHC assay is a reliable method to detect BRAFV600E mutation in PTC and can be used as alternative to molecular methods on routine practice
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Héritier, Sébastien, Jean-François Emile, Mohamed-Aziz Barkaoui, Caroline Thomas, Sylvie Fraitag, Sabah Boudjemaa, Florence Renaud, et al. "BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy." Journal of Clinical Oncology 34, no. 25 (September 1, 2016): 3023–30. http://dx.doi.org/10.1200/jco.2015.65.9508.
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Purpose Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAFV600E mutation occurs frequently, but clinical significance remains to be determined. Patients and Methods BRAFV600E mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. Results Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAFV600E mutation. Patients with BRAFV600E manifested more severe disease than did those with wild-type BRAF. Patients with BRAFV600E comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAFV600E mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAFV600E more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). Conclusion In children with LCH, BRAFV600E mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.
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Pamedytyte, Daina, Vaida Simanaviciene, Dalia Dauksiene, Enrika Leipute, Aurelija Zvirbliene, Valdas Sarauskas, Albertas Dauksa, Rasa Verkauskiene, and Birute Zilaitiene. "Association of microRNA Expression and BRAFV600E Mutation with Recurrence of Thyroid Cancer." Biomolecules 10, no. 4 (April 17, 2020): 625. http://dx.doi.org/10.3390/biom10040625.
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Many miRNAs and cancer-related mutations have been proposed as promising molecular markers of papillary thyroid carcinoma (PTC). However, there are limited data on the correlation between miRNA expression, BRAFV600E mutation, and PTC recurrence. Therefore, to evaluate the potential of BRAFV600E mutation and five selected miRNAs (-146b, -222, -21, -221, -181b) in predicting PTC recurrence, these molecular markers were analyzed in 400 formalin-fixed, paraffin-embedded PTC tissue specimens. The expression levels of miRNAs were measured using qRT-PCR. It was demonstrated that expression levels of all analyzed miRNAs are significantly higher in recurrent PTC than in non-recurrent PTC (p < 0.05). Moreover, higher expression levels of miR-146b, miR-222, miR-21, and miR-221 were associated with other clinicopathologic features of PTC, such as tumor size and lymph node metastases at initial surgery (p < 0.05). No significant differences in the frequency of BRAFV600E mutation in recurrent PTC and non-recurrent PTC were determined. Our results suggest that miRNA expression profile differs in PTC that is prone to recurrence when compared to PTC that does not reoccur after the initial surgery while BRAFV600E mutation frequency does not reflect the PTC recurrence status. However, the prognostic value of the analyzed miRNAs is rather limited in individual cases as the pattern of miRNA expression is highly overlapping between recurrent and non-recurrent PTC.
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Hardee, Steven, Manju L. Prasad, Pei Hui, Catherine A. Dinauer, and Raffaella A. Morotti. "Pathologic Characteristics, Natural History, and Prognostic Implications of BRAFV600E Mutation in Pediatric Papillary Thyroid Carcinoma." Pediatric and Developmental Pathology 20, no. 3 (February 8, 2017): 206–12. http://dx.doi.org/10.1177/1093526616689628.
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The BRAFV600E mutation is the most common genetic aberration in papillary thyroid cancer (PTC), found in up to 68% of PTC in adults where it is associated with aggressive features. The incidence of this mutation in pediatric PTC is less frequent, reported as 0%–20% in the past and up to 63% in one recent series. Data suggest the mutation is not associated with an aggressive course in children; however, there are limited numbers of reported case series, so the prognostic implications remain poorly understood. The aim of this retrospective study was to examine the histologic characteristics and clinical outcomes of BRAF positive pediatric PTC at a single institution. A 12-year retrospective review of all thyroidectomies performed at a tertiary medical center identified 59 pediatric cases with a surgical pathology diagnosis of PTC. Fifty patients had BRAFV600E mutation analysis data and were selected for further study. BRAFV600E mutations were present in 48% of cases (n = 24) and absent in 52% (n = 26). The molecular characteristics of the BRAF negative cases will further be evaluated in future studies. BRAF positive cases occurred in patients who were on average older than the BRAF negative patients. Classic histology PTC was present in both BRAF positive and negative cases; however, only cases with classic PTC histology were positive for the mutation. No patients died and BRAF mutation was not associated with an increased recurrence rate. Our study supports BRAFV600E is more common in children than previously thought and does not portend a more aggressive clinical course.
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Gadde, Samata. "Lack of the BRAFV600E Mutation in Oral Squamous Cell Carcinoma." Journal of Medical Science And clinical Research 04, no. 12 (December 25, 2016): 14912–16. http://dx.doi.org/10.18535/jmscr/v4i12.99.
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Yoon, Jiyoung, Eunjung Lee, Ja Seung Koo, Jung Hyun Yoon, Kee-Hyun Nam, Jandee Lee, Young Suk Jo, Hee Jung Moon, Vivian Youngjean Park, and Jin Young Kwak. "Artificial intelligence to predict the BRAFV600E mutation in patients with thyroid cancer." PLOS ONE 15, no. 11 (November 25, 2020): e0242806. http://dx.doi.org/10.1371/journal.pone.0242806.
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Purpose To investigate whether a computer-aided diagnosis (CAD) program developed using the deep learning convolutional neural network (CNN) on neck US images can predict the BRAFV600E mutation in thyroid cancer. Methods 469 thyroid cancers in 469 patients were included in this retrospective study. A CAD program recently developed using the deep CNN provided risks of malignancy (0–100%) as well as binary results (cancer or not). Using the CAD program, we calculated the risk of malignancy based on a US image of each thyroid nodule (CAD value). Univariate and multivariate logistic regression analyses were performed including patient demographics, the American College of Radiology (ACR) Thyroid Imaging, Reporting and Data System (TIRADS) categories and risks of malignancy calculated through CAD to identify independent predictive factors for the BRAFV600E mutation in thyroid cancer. The predictive power of the CAD value and final multivariable model for the BRAFV600E mutation in thyroid cancer were measured using the area under the receiver operating characteristic (ROC) curves. Results In this study, 380 (81%) patients were positive and 89 (19%) patients were negative for the BRAFV600E mutation. On multivariate analysis, older age (OR = 1.025, p = 0.018), smaller size (OR = 0.963, p = 0.006), and higher CAD value (OR = 1.016, p = 0.004) were significantly associated with the BRAFV600E mutation. The CAD value yielded an AUC of 0.646 (95% CI: 0.576, 0.716) for predicting the BRAFV600E mutation, while the multivariable model yielded an AUC of 0.706 (95% CI: 0.576, 0.716). The multivariable model showed significantly better performance than the CAD value alone (p = 0.004). Conclusion Deep learning-based CAD for thyroid US can help us predict the BRAFV600E mutation in thyroid cancer. More multi-center studies with more cases are needed to further validate our study results.
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Maaitah, Alaa Al, Moaath Alsmady, Shatha Dmour, Dana Alsmady, Ahmad Al Alwan, Mira Younis, Mohammad Al Shhab, et al. "The Prevalence and Prognostic Value of BRAFV600E Mutation in Papillary Thyroid Cancer." International Journal of Human and Health Sciences (IJHHS) 3, no. 4 (September 1, 2019): 223. http://dx.doi.org/10.31344/ijhhs.v3i4.106.
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Objective: B-type Raf kinase (BRAF)V600E mutation in papillary thyroid cancer (PTC) has variable prevalence worldwide and it is hypothesized to worsen tumor prognosis. This study was conducted to investigate the prevalence of BRAFV600E mutation among PTC patients and to find out its prognostic impact measured by its association with various clinicopathologic features, recurrence, and mortality.Methods: This is a retrospective study that included 123 PTC patients who underwent thyroidectomy at Jordan University Hospital between January 2010 and December 2015. They were followed up over a mean of 18 months (range: 4-72). BRAFV600E mutation was analyzed by direct sequencing. A p value less than 0.05 was defined as statistically significant.Results: Twenty three out of 123 (18.7%) PTC patients were BRAFV600E mutation positive. BRAFV600E- mutant patients were more likely to have larger tumor size (1.8 vs 2.5 cm, p=0.040), to present with lymph node metastasis (LNM) (41.2% vs 82.4%, p=0.002), and to develop recurrence (1 vs 3, p=0.0003). Moreover, tumor recurrence which was recorded in 4 patients was significantly associated with LNM (p=0.038). Cancer-specific mortality rate was null.Conclusion: BRAFV600E mutation rate in PTC was low relative to world-wide prevalence. BRAFV600E mutation has prognostic value for PTC management. However, its cost-effectiveness should be revised. Further larger prospective studies in the region are recommended.International Journal of Human and Health Sciences Vol. 03 No. 04 October’19 Page : 223-230
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Acosta-Medina, Aldo A., Jithma P. Abeykoon, N. Nora Bennani, Caroline Davidge-Pitts, Matthew J. Koster, Aishwarya Ravindran, Karen Rech, et al. "BRAFV600E frequency and impact on outcomes in adults with langerhans cell histiocytosis." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 7050. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.7050.
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7050 Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm manifesting as unifocal, multifocal, multisystem (MS) or pulmonary LCH (smoking-related). In pediatric LCH, somatic BRAFV600E prevalence is reported at 55-70%, and associated with increased risk of multisystem disease and early treatment failure. Our aim was to describe the prevalence of BRAFV600E mutation and evaluate its association with clinical manifestations and outcomes in adults with LCH. Methods: A retrospective review of adult patients diagnosed with LCH consecutively seen at Mayo Clinic from 2011 to 2020 was performed.Evaluation of association of BRAFV600E mutational status and clinical factors was conducted by the Chi-square test for independence. Progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan Meier method and compared with the log-rank test to assess the effect of BRAFV600E. Results: Of the total LCH cohort ( n= 128), 88 patients with available BRAFV600E results were included in the study. Median age at diagnosis was 41y (range 19 - 88); 52.3% were male. 40 (45.5%) patients had a BRAFV600E mutation. Increasing age was associated with BRAFV600E (10-year increase OR 1.42, 95%CI 1.07-1.89; p= 0.017). No correlation was observed between BRAFV600E status and site of disease, risk organ (RO: liver, spleen, marrow) involvement, or MS disease. Patients with BRAFV600E were 4 times more likely to receive targeted therapy ( BRAF inhibitor) than non- BRAFV600E patients ( p= 0.018). After a median follow up of 46 mo (95% CI 30.8-61.2), PFS was similar between BRAFV600E and non- BRAFV600E patients ( p= 0.167). However, patients with BRAFV600E had a worse 3-year OS compared with non- BRAFV600E patients (84% vs. 97.1%, p= 0.027). Patients who died had a significantly higher age at LCH diagnosis (median 62 vs. 38 years; p= 0.0002). Conclusions: In our cohort of adults with LCH, BRAFV600E was less frequent than reported in pediatric literature and was associated with worse OS. The frequency of BRAFV600E was positively correlated with increasing age. Contrary to reports in pediatric LCH, there were no significant associations between BRAFV600E and high-risk or multisystem disease.[Table: see text]
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Salem, Mohamed E., Scott Kopetz, Sherif Mohamed El-Refai, Josep Tabernero, Frank A. Sinicrope, Jeanne Tie, Thomas J. George, et al. "Comparative analysis of microsatellite instability-high (MSI-H) BRAF V600E-mutated versus MSI-H BRAFwild type colorectal cancers (CRC), including tumor microenvironment (TME), associated genomic alterations, and immunometabolomic biomarkers." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 3066. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3066.
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3066 Background: The BRAFV600E mutation is associated with the hypermethylator phenotype CIMP, which can also lead to the MSI-H phenotype. BRAFV600E mutation and MSI-H/dMMR status seem to be biologically intertwined; however, the impact of coexisting BRAFV600E mutations on the TME and immunometabolomic features of MSI-H/dMMR CRC tumors is not well characterized. Methods: A retrospective review of deidentified records of patients with MSI-H/dMMR CRC tumors was conducted using next-generation sequencing data (Tempus |xT assay: DNA-seq of 595-648 genes at 500x coverage, and full transcriptome RNA-seq). Several immune markers of tumor immunogenicity in BRAF wild-type ( BRAFwt) vs. V600E-mutated (BRAFV600E) tumors were assessed, including tumor mutational burden (TMB), neoantigen tumor burden (NTB, ScanNeo), PD-L1 expression, immune infiltration, and canonical immuno-metabolomic pathways (82 geneset signatures). Results: A total of 459 MSI-H/dMMR CRC tumors were analyzed, of which 123 (27%) tumors harbored BRAFV600Emutations, and 336 (73%) were BRAFwt. MSI-H/dMMR BRAFV600E tumors were more frequently identified in females (69% vs. 55%; P= 0.01), non-Hispanic or non-Latino (100% vs. 73%; P =0.001), and older patients (median age: 76 yrs vs. 62 yrs; P< 0.001). Compared to BRAFWT, BRAFV600E tumors exhibited significantly higher TMB (Median: 49 mut/MB vs. 36 mut/MB; P < 0.001) and were more frequently associated with TMB-High status (> 10 mut/MB; 100% vs. 95%; P = 0.008); however, no significant differences were observed with tumor NTB, immune score, or T cell infiltration (CD4 or CD8). NK cell infiltration was higher in the BRAFV600Ecohort (< 0.001). When compared to BRAFWT tumors , BRAFV600E tumors harbored a greater frequency of mutations in MSH6(42% vs. 20%), B2M (33% vs. 16%), BRCA2 (31% vs. 12%), ATM (23% vs. 12%), and TP53 (30% vs. 19%) but a lower frequency of MSH2 (3.3% vs. 11%), all P< 0.05. Pathway enrichment analysis identified 10 significantly altered signaling pathways, most of which related to stromal/immune cell signaling and metabolism. Five were upregulated among BRAFV600E tumors: glycerophospholipid, galactose, cyclin-dependent cell signaling; Nucleotide, and TH1 inflammation. Five pathways were downregulated (Wnt, Notch, TH17 inflammation, amino sugar, and cancer stem cell signaling). Conclusions: MSI-H/dMMR BRAFV600E CRCs undergo broad metabolic reprogramming (e.g., glycerophospholipidgalactose, nucleotide). A rise in lipid metabolism, particularly with NK inflammation, suggests that BRAFV600Emutated tumors may be associated with a non-classical immune component. BRAFV600E and BRAFwt CRCs exhibited similar NTB and T cell infiltration, suggesting that both are likely to benefit from immune checkpoint inhibitors.
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Salem, Mohamed E., Scott Kopetz, Sherif Mohamed El-Refai, Josep Tabernero, Frank A. Sinicrope, Jeanne Tie, Thomas J. George, et al. "Comparative analysis of microsatellite instability-high (MSI-H) BRAF V600E-mutated versus MSI-H BRAFwild type colorectal cancers (CRC), including tumor microenvironment (TME), associated genomic alterations, and immunometabolomic biomarkers." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 3066. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3066.
Full textAbstract:
3066 Background: The BRAFV600E mutation is associated with the hypermethylator phenotype CIMP, which can also lead to the MSI-H phenotype. BRAFV600E mutation and MSI-H/dMMR status seem to be biologically intertwined; however, the impact of coexisting BRAFV600E mutations on the TME and immunometabolomic features of MSI-H/dMMR CRC tumors is not well characterized. Methods: A retrospective review of deidentified records of patients with MSI-H/dMMR CRC tumors was conducted using next-generation sequencing data (Tempus |xT assay: DNA-seq of 595-648 genes at 500x coverage, and full transcriptome RNA-seq). Several immune markers of tumor immunogenicity in BRAF wild-type ( BRAFwt) vs. V600E-mutated (BRAFV600E) tumors were assessed, including tumor mutational burden (TMB), neoantigen tumor burden (NTB, ScanNeo), PD-L1 expression, immune infiltration, and canonical immuno-metabolomic pathways (82 geneset signatures). Results: A total of 459 MSI-H/dMMR CRC tumors were analyzed, of which 123 (27%) tumors harbored BRAFV600Emutations, and 336 (73%) were BRAFwt. MSI-H/dMMR BRAFV600E tumors were more frequently identified in females (69% vs. 55%; P= 0.01), non-Hispanic or non-Latino (100% vs. 73%; P =0.001), and older patients (median age: 76 yrs vs. 62 yrs; P< 0.001). Compared to BRAFWT, BRAFV600E tumors exhibited significantly higher TMB (Median: 49 mut/MB vs. 36 mut/MB; P < 0.001) and were more frequently associated with TMB-High status (> 10 mut/MB; 100% vs. 95%; P = 0.008); however, no significant differences were observed with tumor NTB, immune score, or T cell infiltration (CD4 or CD8). NK cell infiltration was higher in the BRAFV600Ecohort (< 0.001). When compared to BRAFWT tumors , BRAFV600E tumors harbored a greater frequency of mutations in MSH6(42% vs. 20%), B2M (33% vs. 16%), BRCA2 (31% vs. 12%), ATM (23% vs. 12%), and TP53 (30% vs. 19%) but a lower frequency of MSH2 (3.3% vs. 11%), all P< 0.05. Pathway enrichment analysis identified 10 significantly altered signaling pathways, most of which related to stromal/immune cell signaling and metabolism. Five were upregulated among BRAFV600E tumors: glycerophospholipid, galactose, cyclin-dependent cell signaling; Nucleotide, and TH1 inflammation. Five pathways were downregulated (Wnt, Notch, TH17 inflammation, amino sugar, and cancer stem cell signaling). Conclusions: MSI-H/dMMR BRAFV600E CRCs undergo broad metabolic reprogramming (e.g., glycerophospholipidgalactose, nucleotide). A rise in lipid metabolism, particularly with NK inflammation, suggests that BRAFV600Emutated tumors may be associated with a non-classical immune component. BRAFV600E and BRAFwt CRCs exhibited similar NTB and T cell infiltration, suggesting that both are likely to benefit from immune checkpoint inhibitors.
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Baldari, Silvia, Giuliana Di Rocco, Marie C. Heffern, Timothy A. Su, Christopher J. Chang, and Gabriele Toietta. "Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells." Cancers 11, no. 5 (May 12, 2019): 659. http://dx.doi.org/10.3390/cancers11050659.
Full textAbstract:
High affinity copper binding to mitogen-activated protein kinase kinase 1 (MAP2K1, also known as MEK1) allosterically promotes the kinase activity of MEK1/2 on extracellular signal regulated kinases 1 and 2 (ERK1/2). Consequently, copper-dependent activation of the mitogen-activated (MAP) kinase pathway has a role in promoting tumor growth. Conversely, copper chelation may represent a possible therapeutic approach for a specific subset of tumors characterized by activating mutations in the serine/threonine protein kinase V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF), such as the V600E, occurring within the kinase domain (BRAFV600E). Tetrathiomolybdate (TM) is a specific copper chelating agent currently used for the treatment of Wilson’s disease and in preclinical studies for the management of metastatic cancers owing to its anti-angiogenic and anti-inflammatory properties. We evaluated in vitro and in vivo the effects of copper depletion achieved by pharmacological treatment with TM in human colorectal cells bearing the BRAFV600E mutation in comparison with BRAF wild type cells. We provide evidence that selective copper chelation differentially affects proliferation, survival and migration of colon cancer cells bearing the BRAFV600E mutation compared to BRAFwt acting via differential phosphorylation levels of ERK1/2. Moreover, tetrathiomolybdate treatment was also effective in reducing the clonogenic potential of colon cancer BRAFV600E cells resistant to BRAF pharmacological inhibition. In conclusion, these results support further assessment of copper chelation therapy as an adjuvant therapy for inhibiting the progression of colon cancers containing the BRAFV600E mutation.
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Wieczorek-Szukala, Katarzyna, Janusz Kopczynski, Aldona Kowalska, and Andrzej Lewinski. "Snail-1 Overexpression Correlates with Metastatic Phenotype in BRAFV600E Positive Papillary Thyroid Carcinoma." Journal of Clinical Medicine 9, no. 9 (August 21, 2020): 2701. http://dx.doi.org/10.3390/jcm9092701.
Full textAbstract:
The ability of cancer to metastasize is regulated by various signaling pathways, including transforming growth factor β (TGFβ), also implicated in the upregulation of Snail-1 transcription factor in malignant neoplasms. B-type Raf kinase gene (BRAF)V600E, the most common driving mutation in papillary thyroid carcinoma (PTC), induces epithelial to mesenchymal transition (EMT) in thyroid cancer cells through changes in the Snail-1 level, increasing cell migration and invasion. However, little is known about the mechanism of Snail-1 and BRAFV600E relations in humans. Our study included 61 PTC patients with evaluated BRAFV600E mutation status. A total of 18 of those patients had lymph node metastases—of whom 10 were BRAFV600E positive, and 8 negative. Our findings indicate that the expression of Snail-1, but not TGFβ1, correlates with the metastatic phenotype in PTC. This is the first piece of evidence that the upregulation of Snail-1 corresponds with the presence of BRAFV600E mutation and increased expression of Snail-1 in metastatic PTC samples is dependent on BRAFV600E mutation status.
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Choden, Sonam, Somboon Keelawat, Chan Kwon Jung, and Andrey Bychkov. "VE1 Immunohistochemistry Improves the Limit of Genotyping for Detecting BRAFV600E Mutation in Papillary Thyroid Cancer." Cancers 12, no. 3 (March 5, 2020): 596. http://dx.doi.org/10.3390/cancers12030596.
Full textAbstract:
Detection of BRAFV600E is useful for making diagnosis and risk stratification of papillary thyroid carcinoma (PTC). Molecular testing, however, is not always available for routine clinical use. To assess the clinical utility and reliability of VE1 immunohistochemistry (IHC) for detecting BRAFV600E mutation in PTC, VE1 IHC was performed on the tissue microarrays of 514 patients with PTC and was compared with Sanger sequencing results. Of 514 PTC cases, 433 (84.2%) were positive for VE1 expression. Among 6 discordant cases between VE1 IHC and Sanger sequencing, 3 initial VE1-false negative cases turned out to be true false negative on repeat testing, and 3 VE1-false positive cases showed BRAFV600E mutation using digital PCR analysis. PTCs with low variant allele fraction were positive for VE1 IHC but were not detected using sequencing. VE1 IHC showed 99.3% sensitivity, 100% specificity, 100% positive predictive value, and 96.4% negative predictive value. The BRAFV600E mutation was significantly associated with older age, multifocality, extrathyroidal extension, lymph node metastasis, and advanced tumor stage. In conclusion, VE1 IHC is a reliable method for detecting BRAFV600E mutation in PTC specimens.
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Lee, Hey Min, Stefania Napolitano, Van K. Morris, Kunal Rai, John Paul Y. C. Shen, Jennifer S. Davis, Dipen M. Maru, et al. "Epigenetic regulation of the Wnt-signaling pathway in CIMP-H BRAFV600E mCRC." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 110. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.110.
Full textAbstract:
110 Background: BRAFV600E mutation identifies mCRC patients with poor prognosis with only little benefit from standard therapy. Analysis from TCGA revealed that 89% of BRAFV600E CRC tumors were associated with a high CpG island methylator phenotype (CIMP-H), which may result in epigenetic silencing of tumor suppressor genes, while only 29% of BRAF wild-type tumors are CIMP-H. In this study, we define key pathways regulated by global DNA hypermethylation in the context of BRAFV600E mutation. Methods: We analyzed the TCGA Illumina 450k array methylation datasets and RNA-sequencing datasets for 97 CIMP-H CRC tumors (27 BRAFV600E; 69 BRAF WT) identified by five universal CIMP annotations ( p14, p16, MLH1, MINT1, MINT2, MINT31). We defined differential methylation profile according to BRAF mutation status and calculated Spearman correlation between methylation and gene expression to identify CIMP-H BRAF-associated genes. Next, pathways enriched with CIMP-H BRAFV600E tumors were defined using PANTHER pathway analysis. Additionally, β-catenin IHC were conducted on 145 MD Anderson CRC patient samples and compared by CIMP and BRAF status. Results: BRAF mutation is associated with lower rates of APC mutation as has previously been shown (32%, 82%). We identified 6,097 differentially methylated probes by BRAF mutation status (FDR = 10-4), and as expected, our data suggests a higher methylation profile in BRAFV600E mutated tumors compared to BRAF WT. Intriguingly, CIMP-H BRAF-associated genes showed enrichment in the Wnt-signaling and cadherin signaling pathways ( p< 0.0001 (FDR < 0.0001)). Despite the epigenetic Wnt-signaling, nuclear β-catenin expression (as a measure of Wnt activity) in CIMP-H and BRAF tumors remains lower than for non-CIMP, and BRAF wild-type ( p= 0.0003 for comparison of CIMP). Conclusions: Genes under methylation regulation in the BRAF-mutant context showed enrichment in Wnt-signaling pathway. Since BRAFV600E CRC tumors have a low association with APC mutation, this data suggests role of epigenetic regulation of the Wnt-pathway activation. However, as measured by nuclear β-catenin, Wnt activation in these tumors is not as high as traditional APC-mutated CRC tumors. CIMP-H tumors with BRAFV600E mutation is a unique subset of CRC tumor that have Wnt-pathway activation regulated by epigenetic modifications more than a β-catenin activation.