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Menzer, Christian, Alexander M. Menzies, Matteo S. Carlino, et al. "Targeted Therapy in Advanced Melanoma With Rare BRAF Mutations." Journal of Clinical Oncology 37, no. 33 (2019): 3142–51. http://dx.doi.org/10.1200/jco.19.00489.
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PURPOSE BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K–mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited. METHODS In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed. RESULTS Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively ( P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma. CONCLUSION Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.
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Lee, Darren, Yazan Abu-Shihab, Deedra Nicolet, et al. "BRAF-Mutated Acute Myeloid Leukemia (AML) Represents a Prognostically Poor Subgroup Enriched for Myelodysplasia-Related Subtypes and Distinct from Other RAS Pathway Mutant AML." Blood 144, Supplement 1 (2024): 2921. https://doi.org/10.1182/blood-2024-210110.
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Background: MAPK/RAS signaling pathway mutations are common somatic events in de novo and secondary acute myeloid leukemia (AML), occurring mainly in NRAS, KRAS, and/or PTPN11. BRAF mutations occur with lower frequency in AML and are reported to be universally associated with poor outcome. To date, no comprehensive analysis exists that decisively assesses clinical and molecular characteristics of BRAF-mutated (BRAFm) AML, including insights into clonal architecture, co-occurring mutations, and disease immunophenotype. Methods: We identified 42 AML pts harboring BRAF mutations through targeted molecular profiling of patients (pts) from our cooperative group frontline trials (Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology, enriched for de novo AML) and large comprehensive cancer centers (enriched for relapsed/refractory (R/R) and secondary AML). All pts had detailed clinical annotations, cytogenetic information, and NGS-based targeted sequencing data available. Six BRAFm pts underwent additional genomic profiling including paired whole exome sequencing and total transcriptome sequencing. To delineate clonal composition and cell states in BRAFm AML, 9 pt samples were characterized using single-cell DNA+Protein multi-omic profiling. Results: Our study cohort included 42 BRAFm pts with newly diagnosed (n=19, 45%), R/R (n=8, 19%) and secondary AML (n=15, 36%), with a median age of 67 years (range 19-84). BRAF mutations were most common in cases of myelodysplasia-related (MR)-AML (WHO 5th edition), accounting for 32 (76%) pts. Bulk NGS suggested that BRAF mutations were either dominant clonal or subclonal events, with variant allele frequency (VAF) of 1-83%. Interestingly, the majority (n=30, 71%) of pts had non-V600 BRAF mutations, instead harboring non-canonical mutations including G469 (n=12), D594 (n=7) and others (n=12). The most frequent co-occurring mutations were in TET2 (36%), ASXL1 (33%), NRAS (29%) and KRAS (26%). Whole exome sequencing revealed that BRAFm AML samples harbored a median mutational burden of 15 non-synonymous coding variants (range, 9-30), including 3 MR mutations and 6 RAS-pathway mutations. Single-cell multi-omic analysis revealed that BRAF mutations can co-occur with other RAS pathway mutations, including NRAS and KRAS, on a single cell level. However, PTPN11 mutations were found in mutually exclusive clones to BRAF mutations. Moreover, we found that BRAFm clones can exist in multiple differentiation states, including CD34+ and CD11b+ compartments unlike FLT3- or other RAS- mutant clones which show strong genotype-immunophenotype correlations. Functional studies have also evaluated the impact of the non-canonical BRAF mutations on clonal fitness and disease development. Clinically, BRAFm pts were treated with high-intensity (HI)+/-venetoclax (VEN), [n=15, 42%], low intensity [LI, n=10, 29%] or LI+VEN [n=10, 29%] regimens. BRAFm AML pts had extremely poor survival, regardless of therapy with an overall composite remission (CR+CRi) rate of 39%. The entire cohort had a median overall survival (OS) of 7 months with a majority (n=31/35, 89%) of pts deceased at last follow-up. The median survival for the newly diagnosed cohort was 14 months. No significant differences in OS were observed based on treatment regimen. Importantly, we found no correlation between BRAF variant allele burden and OS. Given the enrichment of BRAF mutations in MR-AML, we assessed if RAS pathway mutations generally represented poor outcome prognosticators in this subgroup. Analysis of a control cohort of MR-AML pts with (n=129) and without (n=403) RAS pathway mutations treated on cytarabine/daunorubicin-based frontline protocols revealed no survival difference between mutated and wild-type pts. This finding suggests the negative survival impact observed in BRAFm AML pts is specifically due to the presence of the BRAF mutation. Conclusions: BRAF mutations are associated with poor prognosis regardless of clonal burden, without significant therapeutic advantage of currently available treatments. Our profiling results suggest that while BRAFm AML may harbor a RAS pathway addiction, BRAF mutations have distinct impacts compared to other RAS pathway mutations. Our findings highlight the need to further understand the role of BRAF mutations in AML pathogenesis and assess the utility of novel therapeutic strategies in BRAFm AML.
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Xiao, Wenxuan, Ying Liu, Lei Hou, et al. "Retrospective study of BRAF inhibitor-based therapy in patients with BRAF mutated advanced solid tumors (RBAST study)." Journal of Clinical Oncology 42, no. 16_suppl (2024): e23265-e23265. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e23265.
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e23265 Background: BRAF mutations are frequently found in melanoma, non-small cell lung cancer (NSCLC), thyroid cancer, to a lesser degree in other tumor types. These mutations constantly activate the kinase domain and result in MAPK pathway hyperactivation. Successful inhibition of this pathway with BRAF/MEK inhibitors (BRAFi/MEKi) results in a clinically meaningful benefit for some patients. The RBAST study, to assess the efficacy and survival outcomes of BRAF inhibitor-based therapy were investigated in patients with solid tumors harboring BRAF mutations. Methods: Data was collected on a total of 697 cases of solid tumor throughout China between Sep 2018 and Dec 2023. Next Generation Sequencing (NGS) is based on the sequencing of tissue samples. Among the samples, the primary endpoints of this study were objective response rate (ORR), disease control rate (DCR), progress-free survival (PFS) and overall survival (OS). The impact of co-mutations with other genes and BRAF variant allele frequency on treatment efficacy was also assessed in this study. Results: BRAF mutations were detected in 36 cases and 15 patients received BRAFi based therapy were identified. For patients who received BRAFi therapy, the best ORR was 26.7% with 4 patients recorded partial response (PR). There were 2 patients with progressive disease giving a DCR of 86.7%. Responses were observed in 4 types of tumors. PR was observed in patients with colorectal cancer (CRC) and melanoma. Median PFS (mPFS) and median OS (mOS) of these patients were 6.0 months (95% CI: 2.3-7.0) and 17.1 months (95% CI: 4.4-NA), respectively. The co-occurring mutation rates of TP53, PTEN, FAT2 and NF1 were 40% (6/15), 20% (3/15), 20% (3/15) and 13.3% (2/15), respectively. No significant difference (p>0.05) in PFS and OS was observed in any co-occurrence of mutations. BRAF mutation variant allele frequency is not an independent prognostic factor for survival with patients received BRAF inhibitor treatment (p>0.05). Conclusions: To the best of our knowledge, this is the first retrospective study exploring BRAFi treatment effectiveness to BRAF mutated solid tumors for Chinese patients. Treatment with BRAF inhibitors is effective for BRAF mutated advanced solid tumors with DCR of 86.7%, mPFS of 6.0 months and mOS of 17.1 months. Co-mutations with other genes and BRAF variant allele frequency did not impact survival outcomes.
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Prophet, Malshundria, Kun Xiao, Theodore Stewart Gourdin, et al. "Detection of actionable BRAF missense mutations by ctDNA-based genomic analysis in prostate cancer." Journal of Clinical Oncology 36, no. 6_suppl (2018): 306. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.306.
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306 Background: Activating BRAF fusion proteins are rare in prostate cancer (PCa) patients. Driver missense BRAF mutations have not been reported in detail in this population. Methods: We examined ctDNA-derived genomic profiles (Guardant 360) from 2,721 unique PCa patients, to identify BRAF genomic anomalies (SNVs, amplification). The ctDNA results were compared with PCa tissue-based genomics from the TCGA database (1,851 unique patients). Results: BRAF missense mutations were found in 76 ctDNA patients (2.8%) and were from all known mutation classes (I, II, III) as well as variants of unknown significance (VUSs). Only 4 patients had the V600E mutation. Multiple examples of known, autonomously active, non-canonical mutations were found (27), including K601E (12), G469A (5), D594G (2), and G466E (2). There were 45 VUSs. Mutations were primarily clonal but subclonal mutations were also found. In addition BRAF was commonly amplified, usually in the presence of multiple other amplified genes. BRAF missense mutations were more common with ctDNA than TCGA (2.8% vs 1.4%). Neither dataset identified frequent V600E mutations (ctDNA: 4/2,721; TCGA 1/1,851). However patients with the same non-canonical BRAF mutations were found in each dataset (K601E, G469A, G466E, D594G). Each dataset contained unique mutations found in only one patient. BRAF mutations potentially treatable with BRAF or MEK inhibitors (class I, II) were about half of all mutations (ctDNA 40.8%; TCGA 50%). We treated a PCa patient with a clonal BRAF(G469A) mutation with targeted therapy. The patient was resistant to multiple lines of hormonal and cytotoxic therapy. Trametinib produced a clinical and RECIST response. Conclusions: ctDNA-based genomic analysis identified multiple BRAF amplifications and missense SNVs in PCa patients. SNVs are largely non-canonical, but include known activating mutations that could act as drivers. The analysis also identified more BRAF missense mutations than did tissue genomic profiling, but the mutational landscape, overall frequency of mutations was similar with either method. ctDNA-based genomic profiling can identify actionable BRAF driver mutations that may respond to MEK and BRAF inhibitors.
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Hwang, Tae Sook, Wook Youn Kim, Hye Seung Han, et al. "Preoperative RAS Mutational Analysis Is of Great Value in Predicting Follicular Variant of Papillary Thyroid Carcinoma." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/697068.
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Follicular variant of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often causes a diagnostic dilemma. We reconfirmed the molecular profiles in a large number of FVPTCs and investigated the efficacy of the preoperative mutational analysis in indeterminate thyroid nodules. BRAF V600E/K601E and RAS mutational analysis was performed on 187 FVPTCs. Of these, 132 (70.6%) had a point mutation in one of the BRAF V600E (n=57), BRAF K601E (n=11), or RAS (n=64) genes. All mutations were mutually exclusive. The most common RAS mutations were at NRAS codon 61. FNA aspirates from 564 indeterminate nodules were prospectively tested for BRAF and RAS mutation and the surgical outcome was correlated with the mutational status. Fifty-seven and 47 cases were positive for BRAF and RAS mutation, respectively. Twenty-seven RAS-positive patients underwent surgery and all except one patient had FVPTC. The PPV and accuracy of RAS mutational analysis for predicting FVPTC were 96% and 84%, respectively. BRAF or RAS mutations were present in more than two-thirds of FVPTCs and these were mutually exclusive. BRAF mutational analysis followed by N, H, and KRAS codon 61 mutational analysis in indeterminate thyroid nodules would streamline the management of patients with malignancies, mostly FVPTC.
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Stockman, David, Michael T. Tetzlaff, Tariq Al-Zaid, et al. "Differential clinical associations of BRAF and NRAS mutations among histologic types of cutaneous melanomas." Journal of Clinical Oncology 31, no. 15_suppl (2013): e20034-e20034. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e20034.
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e20034 Background: Previous studies have investigated whether BRAF and NRAS mutation status in melanoma correlate with histologic parameters and overall survival (OS), but evaluation of mutation groups irrespective of specific mutation among histologic types of melanoma has led to variability in the reproducibility of results. We tested the hypothesis that different histologic types of melanoma (nodular [NM] and superficial spreading [SSM]) have distinct clinical associations with specific BRAF and NRAS mutations. Methods: Primary tumor histology, BRAF/NRAS mutation status, and clinical outcomes were collected for 195 patients (pts) with stage III or IV disease. Clinical associations with specific mutations were determined separately for patients with NM (n=105) and SSM (n=90) histologic types of primary cutaneous melanomas. Results: Mutational status in NM: 69 BRAF (66%), 19 NRAS (18%), & 17 wild-type (WT;16%). Specific BRAF mutations in NM: V600E 50 (75%), V600K 13 (19%), V600R 4 (6%). Specific NRAS mutations in NM: Q61K 6 (32%), Q61L 2 (11%), Q61R 8 (42%); other 3 (16%). Mutation status in SSM: 45 BRAF (50%), 24 NRAS (27%), 21 WT (23%). Specific BRAF mutations in SSM: V600E 32 (71%), V600K 12 (24%), V600R 0. Specific NRAS mutations in SSM: Q61K 2 (8%), Q61L 5 (21%), Q61R 12 (50%). The distribution of specific BRAF (p=0.21) and NRAS (p=0.29) mutations between NM and SSM was not significantly different. Among NM pts, pts with activating NRAS mutations had shorter OS from the diagnosis of Stage IV melanoma than WT (HR 3.42, p=0.02) and BRAF (HR 2.40, p=0.009). There was no significant difference for BRAF pts vs WT (HR 1.43, p=0.47). Among SSM patients, neither NRAS (HR 1.3, p=0.53) nor BRAF(HR 0.54, p=0.16) were significantly associated with OS compared to WT. Comparison of patients with BRAF V600E vs V600K showed significant association for OS from stage 4 in SSM pts (HR 0.24, p=0.01), but not in NM pts (HR 0.64, p=0.36). Conclusions: The prognostic significance of BRAF and NRAS mutations on OS from stage IV differed for pts with NM and SSM primaries. Further investigation of the histologic types of melanoma with specific BRAF and NRAS mutations in a larger series is necessary to validate these apparent impacts on patient outcomes.
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Brinzan, Costel, Mariana Aschie, Catalin Nicolae Grasa, Anca Florentina Mitroi, Elena Matei, and Georgeta Camelia Cozaru. "The Mutation Profiles of KRAS and BRAF Genes in a Romanian Colorectal Cancer Cohort." Revista de Chimie 70, no. 4 (2019): 1346–50. http://dx.doi.org/10.37358/rc.19.4.7124.
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Colorectal cancer (CRC) is one of most commonly diagnosed malignancies and management of CRC differs in according with patient�s characteristics, tumor type, differentiation, metastatic extension and KRAS/BRAF mutations. Based on this knowledge, we examined the relationship between KRAS/BRAF mutations in paraffin-embedded tumor specimens and some clinicopathological features at CRC in order to provide reliable results to the oncologists and so to contribute to the best care provided to the patients. A 56 of colorectal cancer samples were analyzed for the KRAS and BRAF mutational status using StripAssay method from ViennaLab, Austria. Assays for identification of KRAS/BRAF mutations were based on polymerase chain reaction (PCR) and reverse-hybridization. KRAS mutations were present in 50% (28 patients) of all analyzed CRC and were located in codons 12, 13 and 61. The most frequent types of mutations were substitution of glycine to valine in codon 12 (c.35G]T; 9/28), followed by glycine to aspartate on codon 13 (c.38G]A; 5/28). BRAF mutations were detected at 9 patients (16%) and in all cases Val600Glu mutation has been observed. In one case we reported a concomitant KRAS/BRAF mutation. According with current data, KRAS and BRAF mutations are associated with a poor patient prognosis in CRC, but KRAS mutation in codon 13 and BRAF appear to have a higher oncogenic potential.
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Ahn, Hyo Yeong, Chang Hun Lee, Min Ki Lee, et al. "BRAF V600E Mutation of Non-Small Cell Lung Cancer in Korean Patients." Medicina 59, no. 6 (2023): 1085. http://dx.doi.org/10.3390/medicina59061085.
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Background and Objectives: BRAF mutational status in resected non-small cell lung cancer (NSCLC) in the Korean population is poorly understood. We explored BRAF (particularly BRAF V600E) mutational status among Korean patients with NSCLC. Materials and Methods: This study included 378 patients with resected primary NSCLC who were enrolled from January 2015 to December 2017. The authors obtained formalin-fixed paraffin-embedded (FFPE) tissue blocks and performed peptide nucleic acid (PNA)-clamping polymerase chain reaction (PCR) for detecting BRAF V600, real-time PCR for detecting BRAF V600E, and immunohistochemical analyses using the mutation-specific Ventana VE1 monoclonal antibody. For positive cases in any methods mentioned above, direct Sanger sequencing was additionally performed. Results: The PNA-clamping method revealed the BRAF V600 mutation in 5 (1.3%) of the 378 patients. Among these five patients, real-time PCR, direct Sanger sequencing detected BRAF V600E mutations in three (0.8%) patients. Thus, two cases showed differences in their PNA-clamping and the others. Direct Sanger sequencing of PNA-clamping PCR product was performed for two cases showing negative results on direct Sanger sequencing; both contained BRAF mutations other than V600E. All patients harboring BRAF mutations had adenocarcinomas, and all patients with V600E mutation exhibited minor micropapillary components. Conclusions: Despite the low incidence of the BRAF mutation among Korean patients with NSCLC, lung adenocarcinoma patients with micropapillary components should be prioritized in terms of BRAF mutation testing. Immunohistochemical staining using Ventana VE1 antibody may serve as a screening examination for BRAF V600E.
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Zhang, Jianqing, Jiagang Feng, Ling Liu, et al. "Abstract 5774: Investigating the characteristics of BRAF Mutations and its potential relationship with therapy in a large Chinese Lung Cancer cohort." Cancer Research 82, no. 12_Supplement (2022): 5774. http://dx.doi.org/10.1158/1538-7445.am2022-5774.
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Abstract Background: In lung cancer, the proportion of BRAF mutations is low. Rare specific studies have evaluated the BRAF mutation characteristics in lung cancer. Currently, there are some studies suggesting that patients with BRAF mutations may be benefit from immunotherapy, while patients with BRAF V600E may benefit from targeted therapy. Here, the characteristics of BRAF mutation, including BRAF V600E, in a lung cancer cohort of Chinese were analyzed. The characteristics of BRAF mutation with PD-L1 expression were also analyzed. Method: BRAF mutant samples were extracted from 12,051 our cohort samples of lung cancer that from Onco Panscan࣪ (Genetron Health) based sequencing of tissue. The characteristics of them were then investigated. Co-mutations of PD-L1 expressed BRAF samples were also analyzed. Results: 684 samples (5.68%) in our cohort had BRAF mutations. Only 134 (19.59%) of them were V600E mutation, maybe good response to BRAF inhibitors. 550 (80.41%) of samples were BRAF non-V600E mutation, maybe benefit from immunotherapy. BRAF mutations were more happened in male (58.3%), while female patients were increased in V600E mutation group when compared with non-V600E group (49.25% vs. 39.82%, P=0.0509). BRAF mutations were more likely to occur in LUAD than in LUSC (6.37% vs. 3.89%, P=0.0022), especially BRAF V600E mutation. The mean age of BRAF mutant patients was 61.56 ± 10.32 years. BRAF V600E patients was significantly older than BRAF non-V600E patients on average (63.01 ± 9.76 years vs. 61.20 ±10.43, P=0.0129). BRAF mutations were distributed across all exons but concentrated on exon 15 (269/684, 39.33%). Moreover, BRAF V600E mutation accounted for 49.81% (134/269) of exon 15. In our data, there were 108 samples with BRAF mutation and PD-L1 positive (TPS≥1%). Among them, 95 samples (87.96%), including samples with BRAF V600E or non-V600E mutation, had no co-mutations or without other medication targets, may be benefit from BRAF inhibitors, or may be good response to immunotherapy, especially the 20 samples with TMB-high. Interestingly, 13 samples had EGFR sensitive co-mutation or EML4-ALK fusion. These 13 patients may be benefit from TKI firstly, then immunotherapy can be considered. Conclusions: Most of BRAF mutations in Chinese lung cancer samples were non-V600E mutations (80.26%). BRAF mutations were more occurred in male and LUAD patients whose age around 61.56 ± 10.32 years. BRAF V600E patients were much older. Among PD-L1 positive and BRAF mutant samples, most BRAF mutations (87.96%), including V600E, were mutually exclusive with driver mutations of other genes. These patients will most likely benefit from BRAF inhibitors or immunotherapy. For the samples with co-mutation of BRAF and EGFR or ALK, may be treated EGFR or ALK TKI firstly. Citation Format: Jianqing Zhang, Jiagang Feng, Ling Liu, Man Jia, Tong Liu, Jiaqiang Zhang, Zehua Liao, Jianmei Zhao, Yu Fang, Jing Chen, Xiaoyan Zhang, Tonghui Ma. Investigating the characteristics of BRAF Mutations and its potential relationship with therapy in a large Chinese Lung Cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5774.
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Lee, Joon-Hyop, Jiyoung Ahn, Won Seo Park, et al. "Colorectal Cancer Prognosis is Not Associated with BRAF and KRAS Mutations-A STROBE Compliant Study." Journal of Clinical Medicine 8, no. 1 (2019): 111. http://dx.doi.org/10.3390/jcm8010111.
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Background: We investigated the associations between v-Raf murine sarcoma viral oncogene homolog B1 (BRAFV600E, henceforth BRAF) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and colorectal cancer (CRC) prognosis, using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GSE39582) datasets. Materials and Methods: The effects of BRAF and KRAS mutations on overall survival (OS) and disease-free survival (DFS) of CRC were evaluated. Results: The mutational status of BRAF and KRAS genes was not associated with overall survival (OS) or DFS of the CRC patients drawn from the TCGA database. The 3-year OS and DFS rates of the BRAF mutation (+) vs. mutation (−) groups were 92.6% vs. 90.4% and 79.7% vs. 68.4%, respectively. The 3-year OS and DFS rates of the KRAS mutation (+) vs. mutation (−) groups were 90.4% vs. 90.5% and 65.3% vs. 73.5%, respectively. In stage II patients, however, the 3-year OS rate was lower in the BRAF mutation (+) group than in the mutation (−) group (85.5% vs. 97.7%, p <0.001). The mutational status of BRAF genes of 497 CRC patients drawn from the GSE39582 database was not associated with OS or DFS. The 3-year OS and DFS rates of BRAF mutation (+) vs. mutation (−) groups were 75.7% vs. 78.9% and 73.6% vs. 71.1%, respectively. However, KRAS mutational status had an effect on 3-year OS rate (71.9% mutation (+) vs. 83% mutation (−), p = 0.05) and DFS rate (66.3% mutation (+) vs. 74.6% mutation (−), p = 0.013). Conclusions: We found no consistent association between the mutational status of BRAF nor KRAS and the OS and DFS of CRC patients from the TCGA and GSE39582 databases. Studies with longer-term records and larger patient numbers may be necessary to expound the influence of BRAF and KRAS mutations on the outcomes of CRC.
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Thompson, Elizabeth L., Jiayi J. Hu, and Laura J. Niedernhofer. "The Role of Senescent Cells in Acquired Drug Resistance and Secondary Cancer in BRAFi-Treated Melanoma." Cancers 13, no. 9 (2021): 2241. http://dx.doi.org/10.3390/cancers13092241.
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BRAF is the most common gene mutated in malignant melanoma, and predominately it is a missense mutation of codon 600 in the kinase domain. This oncogenic BRAF missense mutation results in constitutive activation of the mitogen-activate protein kinase (MAPK) pro-survival pathway. Several BRAF inhibitors (BRAFi) have been developed to specifically inhibit BRAFV600 mutations that improve melanoma survival, but resistance and secondary cancer often occur. Causal mechanisms of BRAFi-induced secondary cancer and resistance have been identified through upregulation of MAPK and alternate pro-survival pathways. In addition, overriding of cellular senescence is observed throughout the progression of disease from benign nevi to malignant melanoma. In this review, we discuss melanoma BRAF mutations, the genetic mechanism of BRAFi resistance, and the evidence supporting the role of senescent cells in melanoma disease progression, drug resistance and secondary cancer. We further highlight the potential benefit of targeting senescent cells with senotherapeutics as adjuvant therapy in combating melanoma.
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Moltara, Maja Ebert, Srdjan Novakovic, Marko Boc, et al. "Prevalence of BRAF, NRAS and c-KIT mutations in Slovenian patients with advanced melanoma." Radiology and Oncology 52, no. 3 (2018): 289–95. http://dx.doi.org/10.2478/raon-2018-0017.
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Abstract Background BRAF, NRAS and c-KIT mutations are characteristics of tumour tissues that influence on treatment decisions in metastatic melanoma patients. Mutation frequency and their correlation with histological characteristics in Slovenian population have not been investigated yet. Patients and methods In our retrospective analysis we analysed mutational status of BRAF, NRAS and c-KIT in 230 pathological samples of patients who were intended to be treated with systemic therapy due to metastatic disease at the Institute of Oncology Ljubljana between 2013 and 2016. We collected also histological characteristics of primary tumours and clinical data of patients and correlated them with mutational status of tumour samples. Results The study population consisted of 230 patients with a mean age 59 years (range 25−85). 141 (61.3%) were males and 89 (38.7%) females. BRAF mutations were identified in 129 (56.1%), NRAS in 31 (13.5%) and c-KIT in 3 (1.3%) tissue samples. Among the 129 patients with BRAF mutations, 114 (88.4%) patients had V600E mutation and 15 (11.6%) had V600K mutation. Patients with BRAF mutations tended to be younger at diagnosis (52 vs. 59 years, p < 0.05), patients with NRAS mutations older (61 vs. 55 years, p < 0.05). Number of c-KIT mutations were too low for any statistical correlation, but there was one out of 3 melanoma located in mucus membranes. Conclusions The analysis detected high rate of BRAF mutations, low NRAS mutations and low c-KIT mutations compared to previously published studies in Europe and North America. One of the main reasons for this observation is specific characteristics of study population.
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Chen, Yungchang, Yanhong Deng, Yutong Ma, et al. "Clinical and genomic distinction of class 1/2/3 BRAF-mutant colorectal cancer and differential prognosis." Journal of Clinical Oncology 40, no. 16_suppl (2022): 3533. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3533.
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3533 Background: Mutations occurring at the V600 amino acid of BRAF is the most common BRAF mutations in colorectal cancer (CRC), which lead to RAS-independent active monomers (Class 1) and are the targets of BRAF inhibitors. BRAF non-V600 mutants can be further classified as RAS-independent active dimers (Class 2) and RAS-dependent impaired kinase (Class 3). The clinical and genetic distinction of CRC patients carrying different subtypes of BRAF mutations remain to be revealed. Methods: A multicenter retrospective study investigated the mutational profiles of 2,118 CRC patients whose baseline tumor samples were analyzed between June 2015 and June 2020 using capture-based hybrid NGS targeting 400+ cancer-related genes. Clinical characteristics including age, sex, stage, and tumor location were analyzed. A public cBioPortal cohort of 471 metastatic CRC patients was used for survival analysis. Results: A total of 473 patients were identified to contain BRAF mutations and can be sub-grouped into Class 1 (N = 246), Class 2 (N = 29), Class 3 (N = 53), and others (N = 145). All Class 1 BRAF mutations were V600E, while the Class 2 and Class 3 mutations were predominantly G469 (52%) and D594 (56%), respectively. No difference in patient’s age, sex, and stage was observed among BRAF Class 1-3 subgroups, but the anatomical location of the tumor differed among subgroups, particularly between Class 1 and Class 3 BRAF-mutant patients significantly (p = 0.027). Specifically, 39% of tumors carrying Class 1 mutations occurred at the right colon, while the most frequent location of tumors with Class 3 mutations was rectum (58%). Mutational profiling revealed that KRAS and APC mutations were enriched in Class 2/3 compared to Class 1 BRAF-mutant patients, while RNF43 and SMAD4 mutations were more frequently observed in Class 1 patients. Mutations causing the activation of the Wnt or RTK/RAS signaling pathways were also more common in Class 2/3 subgroups comparing to Class 1 patients. Furthermore, based on the analysis of mutation allele frequency, Class 1 BRAF mutations tended to be drivers while Class 2/3 BRAF mutations were more likely to be passengers. In addition, mutational signature profiling showed that the NER signature was enriched in Class 1 BRAF-mutant patients but the APOBEC signature in Class2/3 classes. The tumor mutational burden of Class 2 BRAF tumors was higher than the other two subgroups (median: 10.4 vs 7.6 and 8.4), and microsatellite instability-high tumors were more common in Class 1 (11% vs 7% and 4%). In the cBioPortal cohort, Class 1 BRAF-mutant patients had the worst overall survival whereas Class 3 patients demonstrated the best prognosis. Conclusions: The clinical and genetic features of CRC patients harboring Class 2 and 3 BRAF mutations were different from those carrying Class 1 BRAF mutations in aspects including tumor location, concurrent mutations, mutational signatures, as well as survival outcomes.
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Röck, Ruth, Johanna E. Mayrhofer, Omar Torres-Quesada, et al. "BRAF inhibitors promote intermediate BRAF(V600E) conformations and binary interactions with activated RAS." Science Advances 5, no. 8 (2019): eaav8463. http://dx.doi.org/10.1126/sciadv.aav8463.
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Oncogenic BRAF mutations initiate tumor formation by unleashing the autoinhibited kinase conformation and promoting RAS-decoupled proliferative RAF-MEK-ERK signaling. We have engineered luciferase-based biosensors to systematically track full-length BRAF conformations and interactions affected by tumorigenic kinase mutations and GTP loading of RAS. Binding of structurally diverse αC-helix-OUT BRAF inhibitors (BRAFi) showed differences in specificity and efficacy by shifting patient mutation–containing BRAF reporters from the definitive opened to more closed conformations. Unexpectedly, BRAFi engagement with the catalytic pocket of V600E-mutated BRAF stabilized an intermediate and inactive kinase conformation that enhanced binary RAS:RAF interactions, also independently of RAF dimerization in melanoma cells. We present evidence that the interference with RAS interactions and nanoclustering antagonizes the sequential formation of drug-induced RAS:RAF tetramers. This suggests a previously unappreciated allosteric effect of anticancer drug-driven intramolecular communication between the kinase and RAS-binding domains of mutated BRAF, which may further promote paradoxical kinase activation and drug resistance mechanisms.
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Jones, Jeremy C., Lindsay A. Renfro, Humaid O. Al-Shamsi, et al. "Non-V600BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer." Journal of Clinical Oncology 35, no. 23 (2017): 2624–30. http://dx.doi.org/10.1200/jco.2016.71.4394.
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Purpose Molecular diagnostic testing has become an integral part of the evaluation of patients with metastatic colorectal cancer (CRC). Expanded mutational testing, such as next-generation sequencing (NGS), often identifies mutations with unclear clinical or prognostic implications. One such example is BRAF mutations that occur outside of codon 600 (non-V600 BRAF mutations). Methods We conducted this multicenter, retrospective cohort study to characterize the clinical, pathologic, and survival implications of non-V600 BRAF mutations in metastatic CRC. We pooled patients in whom non-V600 BRAF mutations were identified from NGS databases at three large molecular genetics reference laboratories. Results A total of 9,643 patients with metastatic CRC underwent NGS testing. We identified 208 patients with non-V600 BRAF mutations, which occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Cancers with non-V600 BRAF mutations, compared with cancers with V600E BRAF (V600E BRAF) mutations, were found in patients who were significantly younger (58 v 68 years, respectively), fewer female patients (46% v 65%, respectively), and patients who had fewer high-grade tumors (13% v 64%, respectively) or right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months, respectively; P < .001). In multivariable analysis, non-V600 BRAF mutation was independently associated with improved overall survival (hazard ratio, 0.18; P < .001). Conclusion Non-V600 BRAF mutations occur in approximately 2.2% of patients with metastatic CRC and define a clinically distinct subtype of CRC with an excellent prognosis.
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Kazandjian, Suzanne, Emmanuelle Rousselle, Matthew Dankner, et al. "The Clinical, Genomic, and Transcriptomic Landscape of BRAF Mutant Cancers." Cancers 16, no. 2 (2024): 445. http://dx.doi.org/10.3390/cancers16020445.
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Background: BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, genomic, and transcriptomic variables in cancer patients. Methods: Using the AACR GENIE (v.12) cancer database, the distribution of BRAF mutation class in adult cancer patients was analyzed according to sex, age, primary race, and tumor type. Genomic alteration data and transcriptomic analysis was performed using The Cancer Genome Atlas. Results: BRAF mutations were identified in 9515 (6.2%) samples among 153,834, with melanoma (31%), CRC (20.7%), and NSCLC (13.9%) being the most frequent cancer types. Class 1 harbored co-mutations outside of the MAPK pathway (TERT, RFN43) vs. Class 2/3 mutations (RAS, NF1). Across all tumor types, Class 2/3 were enriched for alterations in genes involved in UV response and WNT/β-catenin. Pathway analysis revealed enrichment of WNT/β-catenin and Hedgehog signaling in non-V600 mutated CRC. Males had a higher proportion of Class 3 mutations vs. females (17.4% vs. 12.3% q = 0.003). Non-V600 mutations were generally more common in older patients (aged 60+) vs. younger (38% vs. 15% p < 0.0001), except in CRC (15% vs. 30% q = 0.0001). Black race was associated with non-V600 BRAF alterations (OR: 1.58; p < 0.0001). Conclusions: Class 2/3 BRAFs are more present in Black male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help the development of targeted therapies for non-V600 BRAF mutations.
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An, Zhang Quan. "Abstract 2566: Molecular characteristic profile in early colorectal cancer with V600E and non-V600E BRAF mutations." Cancer Research 84, no. 6_Supplement (2024): 2566. http://dx.doi.org/10.1158/1538-7445.am2024-2566.
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Abstract Background: The BRAF V600E mutation in colorectal cancer (CRC) is a significant indicator of poor prognosis, especially in tumors exhibiting microsatellite instability (MSI). It is more common on the right side of the colon but can occur anywhere within the colon. Although other BRAF mutations existed, current research primarily focused on BRAF V600E. Most clinical data sets were centered on advanced colorectal cancer. There was limited understanding of the molecular characteristics of early-stage colorectal cancer patients with BRAF mutations, which impacted postoperative prognosis management, including refining adjuvant therapy regimens. Therefore, we analyzed the molecular characteristics of early-stage CRC surgical patients. Methods: Tumor tissue from 767 early-stage CRC patients diagnosed between 2021 to 2022 in China were analyzed using NGS (panel on 733 gene) to validate the mutation characteristics. Tumor specimens were tested for the BRAF mutation and MSI status. Result: Among 767 early CRC cases tested, BRAF mutations accounted for 6.52% (50/767), with 62% (31/50) being BRAF V600E, followed by 14% (7/50) for BRAF D594G. Notably, there were two cases of fusion variations, TRIM24-BRAF, and one case of BRAF copy gain. Among the BRAF mutation population, 11 cases were MSI-H, with 8 of them being BRAF V600E/MSI-H. Only one MSH-H patient had a germline mutation in the MLH1 gene, with a concurrent mutation in BRAF K601T.Interestingly, when comparing the mutation profiles of the BRAF V600E population with those of the non-V600E BRAF mutation population, we found distinct co-mutated genes despite both being BRAF mutations. In the BRAF V600E group, the top three frequently mutated genes were TP53 (52%), RNF43 (32%), and SMAD4 (32%). Additionally, the BRAF V600E/MSI-H subgroup presented a distinct mutation profile, with minimal occurrences of TP53 and SMAD4 mutations. In the non-V600E BRAF mutation group, the top three frequently mutated genes were TP53 (84%), APC (63%), and KRAS (32%). Conclusions: In examining the mutation profile characteristics of early colorectal cancer with BRAF mutations, the proportion of BRAF V600E/MSI-H appeared to have been lower than that reported in advanced cases. Furthermore, in terms of the frequency of co-mutated genes, it seemed that BRAF V600E had exhibited a higher malignant driving mutation effect as a single gene, while non-V600E mutations had required more cooperative tumor suppressor genes or oncogenes. Analyzing the molecular characteristics of early colorectal cancer patients with V600E and non-V600E BRAF mutations could help improve postoperative management and further our understanding of tumor progression. Citation Format: Zhang Quan An. Molecular characteristic profile in early colorectal cancer with V600E and non-V600E BRAF mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2566.
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Gökmen, İvo, Ebru Taştekin, Nazan Demir, et al. "Molecular Pattern and Clinical Implications of KRAS/NRAS and BRAF Mutations in Colorectal Cancer." Current Issues in Molecular Biology 45, no. 10 (2023): 7803–12. http://dx.doi.org/10.3390/cimb45100491.
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The aim of our study was to evaluate the incidence of KRAS/NRAS and BRAF mutations, analyze molecular patterns, and investigate associations with clinical parameters of these mutations in CRC KRAS/NRAS and BRAF mutations analyzed by next-generation sequencing. The detection rates of these mutations and patients’ demographics were recorded and the relationship between them was evaluated using the chi-square test. KRAS mutation was detected in 332 of 694 patients, while the mutation rates in KRAS exons 2/3 and 4 were 39.6%/3.2% and 5%, respectively. The most common mutation pattern was KRAS G12D. Five atypical variants were detected: V14I in KRAS exon 2, A18D, Q22K and T50I in exon 3, and T148P in exon 4. NRAS mutation was detected in 29 (4.5%) patients. One atypical variant L80W was detected in NRAS exon 3. BRAF mutation was seen in 37 (5.3%) patients, with BRAFV600E (83.8%) being the most common mutation pattern. NRAS mutation was significantly more frequent in patients > 64 years of age, BRAF mutation in women, and NRAS/BRAF mutations in right colon tumors. Grouping BRAF mutations into BRAFV600E and BRAFnon-V600E and their analysis according to specific tumor localizations showed that all four BRAFnon-V600E mutations originated in the rectum. In our study, KRAS exon 2 and other RAS mutation rates were higher than in the literature, while the BRAF v.600E mutation rate was similar. NRAS and BRAF mutations were significantly more frequent in the right colon. BRAF mutation was more common in women and in the right colon.
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Yamazaki, Kentaro, Takayuki Yoshino, Katsuya Tsuchihara, 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 (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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Zhang, Jian, Yu Fang, Lei Sun, et al. "Abstract 5292: Investigating the potential relationship between BRAF mutations and tumor mutation burden (TMB) in lung cancer (LC)." Cancer Research 82, no. 12_Supplement (2022): 5292. http://dx.doi.org/10.1158/1538-7445.am2022-5292.
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Abstract BackgroundCurrently, BRAF inhibitors are primarily effective in LC patients with BRAF V600E mutation, while with limited benefit for patients with BRAF non-V600E mutation. Additionally, it is unclear whether immunotherapy is effective in LC patients with BRAF mutations, and the relationship between BRAF mutations and immune biomarkers, such as TMB, is also unclear. Here, we retrospectively investigated the relationship with BRAF mutation and TMB in Chinese LC patients.MethodsSamples were extracted from 3,136 our cohort samples of LC, which from OncoPanscan࣪ (Genetron Health) based sequencing of tissue. Because of the significantly different cohort characteristics, propensity score matching was used to resolve potential confounding by a nearest neighbor algorithm. The use of a multivariable logistic regression model to estimate the propensity score was based on age, sex, cancer type and detail panels. The samples after propensity score matching was used to investigate the relationship with TMB. ResultsIn our cohort, 171 samples had BRAF mutations and 2,965 samples had non-BRAF mutations. After propensity score analysis, 165 samples of BRAF mutations were screened with 165 paired samples of non-BRAF mutations.In the 165 samples of BRAF mutations, 83 samples of them had TMB information, while 83 samples of the 165 paired samples of non-BRAF mutations had TMB information. Patients with BRAF mutation had a higher median TMB than the patients with non-BRAF mutation (9.39 vs. 7.51 Muts/Mb, p=0.0545). Similarly, in these two groups, there was slightly higher ratio of samples with TMB ≥10muts/Mb (43.37% vs. 31.32%, P=0.0788). Among BRAF mutation group, when compared to BRAF V600E group (N=26), the median TMB was much higher in non-V600E group (N=57) (7.38 vs. 9.86 muts/Mb, P=0.0270). The proportion of TMB ≥10muts/Mb in BRAF non-V600E group was much higher than V600E group (49.12% vs. 30.77%, P=0.0094). Additionally, we analyzed the samples that had high TMB (TMB≥10 muts/Mb) and high PD-L1 (TPS≥50%). The BRAF mutation group had more proportion than non-BRAF mutation (14.46% vs.6.02%, p=0.0593), and the BRAF non-V600E group was higher than BRAF V600E group (15.79% vs. 11.54%, P=0.4150).ConclusionsCompared with non-BRAF mutation, BRAF mutation was associated with higher TMB, and it was also higher in BRAF non-V600E than BRAF V600E. These results suggested that patients with driver mutation of BRAF V600E had lower TMB and they always had good response to BRAF inhibitors. While LC patients with BRAF non-V600E always with higher TMB, thus, they may be more suitable for immunotherapy. However, more clinical research are needed to evaluate the effectiveness of immunotherapy. Citation Format: Jian Zhang, Yu Fang, Lei Sun, Hongling Yuan, Mao Shang, Xiaoyan Zhang, Honglin Zhu, Tonghui Ma. Investigating the potential relationship between BRAF mutations and tumor mutation burden (TMB) in lung cancer (LC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5292.
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Barzon, Luisa, Giulia Masi, Isabella Merante Boschin, et al. "Characterization of a novel complex BRAF mutation in a follicular variant papillary thyroid carcinoma." European Journal of Endocrinology 159, no. 1 (2008): 77–80. http://dx.doi.org/10.1530/eje-08-0239.
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IntroductionActivating mutations of the BRAF oncogene are frequently detected in papillary thyroid carcinoma (PTC) and have been associated with a worse prognosis. The amino acid substitution V600E accounts for 90% of all oncogenic BRAF mutations and is typically detected in classic PTCs, whereas other less frequent BRAF mutations seem to be associated with other PTC histotypes.CaseScreening for activating BRAF mutations in a series of 83 PTCs identified the most common V600E mutation in 39 cases (histologically, 38 classic PTCs and 1 sclerosing variant PTC) and a complex in-frame mutation involving amino acids V600–S605 in a stage III multicentric follicular variant PTC, occurring in a 50-year-old female patient, who was affected by hypothyroidism in autoimmune thyroiditis and had a family history of PTC and autoimmune thyroiditis. Since the identified BRAF mutation was novel in the literature, bioinformatic modeling was performed to predict its impact on BRAF activity. Although the mutation resulted in loss of a phosphorylation site in the activation loop of BRAF, it was predicted to increase BRAF kinase activity by mimicking an activating phosphorylation.ConclusionsThis study, which reports a new BRAF mutation, highlights the usefulness of bioinformatic modeling in the prediction of functional effects of new mutations and indicates that mutation-specific screening tests might miss some rare BRAF mutations. These facts should be taken into consideration in the molecular diagnosis of thyroid cancer and in the design of therapeutic protocols based on inhibitors of the BRAF pathway.
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Di Nicolantonio, Federica, Miriam Martini, Francesca Molinari, et al. "Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer." Journal of Clinical Oncology 26, no. 35 (2008): 5705–12. http://dx.doi.org/10.1200/jco.2008.18.0786.
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Purpose Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. Patients and Methods We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. Conclusion BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.
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Wagner, Sebastian A. "Clinical associations and genetic interactions of oncogenic BRAF alleles." PeerJ 10 (October 18, 2022): e14126. http://dx.doi.org/10.7717/peerj.14126.
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BRAF is a serine/threonine-specific protein kinase that regulates the MAPK/ERK signaling pathway, and mutations in the BRAF gene are considered oncogenic drivers in diverse types of cancer. Based on the signaling mechanism, oncogenic BRAF mutations can be assigned to three different classes: class 1 mutations constitutively activate the kinase domain and lead to RAS-independent signaling, class 2 mutations induce artificial dimerization of BRAF and RAS-independent signaling and class 3 mutations display reduced or abolished kinase function and require upstream signals. Despite the importance of BRAF mutations in cancer, the clinical associations, genetic interactions and therapeutic implications of non-V600 BRAF mutations have not been explored comprehensively yet. In this study, the author analyzed publically available data from the AACR Project GENIE to further understand clinical associations and genetic interactions of oncogenic BRAF mutations. The analyses identified 93 recurrent BRAF mutations, out of which 50 could be assigned to a functional class based on literature review. The author could show that the frequency of BRAF mutations varies across cancer types and subtypes, and that the BRAF mutation classes are unequally distributed across cancer types and subtypes. Using permutation testing-based co-occurrence analyses, the author defined the genetic interactions of BRAF mutations in multiple cancer types and revealed unexplored genetic interactions that might define clinically relevant subgroups. With non-small cell lung cancer as example, the author further showed that the genetic interactions are BRAF mutation class-specific. The presented analyses explore the properties of oncogenic BRAF mutations and will help to further delineate the complex role of BRAF in cancer.
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Chendriadi, Vanesya Rizky, and Willy Sandhika. "Exploiting BRAF Mutation for Treatment of Malignant Melanoma: A Literature Review." International Journal of Research and Review 10, no. 12 (2024): 845–53. http://dx.doi.org/10.52403/ijrr.20231285.
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Malignant melanoma, a deadly type of skin cancer, presents considerable challenges in clinical management. However, the advent of targeted therapies capitalizing on BRAF mutations has ushered in a new era of optimism for treating melanomas. This investigation delves into the utilization of BRAF mutations as a focused approach in addressing malignant melanoma. Anomalously activated RAS-RAF-MEK-ERK signaling, particularly through the prevalent V600E mutation, instigates uncontrolled cell proliferation and survival in melanocytes. Melanoma arises de novo from melanocytes carrying genetic alterations, with RAF mutations being the most common. Mutated RAF genes, notably the V600E mutation, induce dysregulated cell cycle progression, fueling unchecked proliferation. Given that RAF is a pivotal component of the RAS-MAPK pathway, manipulating this pathway emerges as a promising strategy to impede cancer growth. However, not all melanoma cases exhibit RAS mutations, necessitating molecular testing to identify BRAF mutations before initiating targeted therapy. Detecting typically somatic BRAF mutations mandates melanoma tissue as a specimen. The presence of V600E BRAF mutations becomes a crucial factor for employing BRAF inhibitor therapy. This review article underscores the imperative nature of RAF mutation testing in melanoma patients, serving as a predictive tool to determine the cancer's responsiveness to RAF inhibitor treatment. The identification of BRAF mutations offers a targeted therapeutic avenue, instilling fresh hope for personalized and effective interventions in the management of malignant melanoma. Keywords: skin cancer; melanoma; braf mutation
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Rother, J., J. Bailey, G. Alvarado, et al. "Molecular dissection of the RAS/RAF/MAPK pathway in primary and metastatic melanoma." Journal of Clinical Oncology 24, no. 18_suppl (2006): 8050. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.8050.
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8050 Background: Given the reported presence of frequent mutation in NRAS and BRAF in many melanocytic lesions, the association of mutations activating the RAS/RAF/MAPK pathway with tumor progression in melanoma remains unclear. We compared the NRAS and BRAF mutation status with the levels of activated MAPK in paired primary and metastatic melanomas. Methods: 15 patients with material from both primary and metastatic lesions were assessed. Four patients had metastasis at initial diagnosis, the remaining patients developed metastasis from 8.5 to 66 months (mos) following initial diagnosis (median 24.1 mos). Mutations in BRAF (exons 11 and 15) and KRAS and NRAS (exons 1 and 2) were assessed by quantitative pyrosequencing. MAPK levels were assessed by immunohistochemistry on paraffin sections using phosphor-44/42 (Thr202/Tyr204) polyclonal antisera. Results: Activating NRAS point mutations were found in 3 of 15 patients, with 2 detected in the metastatic lesions; both of these had upregulation of activated MAPK compared to the primary lesions. BRAF V599 point mutations were found in 3 of 15 patients and present in both the primary and cognate metastatic lesions. All cases with BRAF or NRAS mutations had moderate to high levels of activated MAPK, as compared to only 2 of 9 patients without such mutations. The correlation of mutational status and clinical course revealed that NRAS/BRAF mutations and/or MAPK activation did not negatively impact overall survival. Conclusions: Molecular alterations in the RAS signaling pathway are associated with activated MAPK in both primary and metastatic melanoma. NRAS mutations and MAPK activation may be preferentially associated with disease progression, as opposed to BRAF mutations. However, neither NRAS/BRAF mutation nor activation of MAPK signaling pathway in primary and/or metastatic melanoma was significantly associated with poor disease outcome. Further molecular dissection using the archived material from two large melanoma neoadjuvant trials conducted in 1988 and 1994 is ongoing to determine the prognostic and predictive power of these biomarkers. No significant financial relationships to disclose.
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Mazurenko, N. N., I. V. Tsyganova, A. A. Lushnikova, et al. "MUTATIONAL STATUS AND SOME CLINICO-MORPHOLOGICAL FEATURES OF CUTANEOUS MELANOMA." Russian Journal of Oncology 22, no. 2 (2017): 60–65. http://dx.doi.org/10.18821/1028-9984-2017-22-2-60-65.
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Cutaneous melanoma is characterized by molecular heterogeneity. The work is devoted to the analysis of mutational status of genes involved in MAPK signaling in primary and metastatic cutaneous melanoma for the detection of tumor sensitivity to the specific targeted therapy as well as possible links of genetic alterations in cutaneous melanoma with some clinical and morphological features. BRAF, NRAS and KIT mutations were found in 60.6%, 13.8% and 1% of cutaneous melanoma cases correspondingly. Mutational status of cutaneous melanoma is differed depending on tumor localization, chronic UV insolation and patients’ age. Thus the rate of the BRAF mutation in melanomas of trunk and extremities (64.7%) was higher than in melanomas of face and head (42.8%). The rate of BRAF mutation was shown to be not associated with pigmentation and tumor growth while NRAS mutation frequency in amelanotic melanoma was lower and in noddle melanoma - higher if compared with pigmented cutaneous melanoma in the radial growth phase. The trend in the association of mutations with melanoma histological type was shown for the first time, the highest rate of BRAF mutation was found in epithelioid melanoma. The obtained results are important for the treatment of cutaneous melanoma as mutational status determines the sensitivity of metastatic melanoma to specific targeted therapy in patients with BRAF, NRAS and KIT mutations.
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Sørensen, Anna Lahn, Mariann Guldmann-Christensen, Michael Børgesen, et al. "Detection of BRAF mutations in malignant melanoma and colorectal cancer by SensiScreen® FFPE BRAF qPCR assay." PLOS ONE 18, no. 2 (2023): e0281558. http://dx.doi.org/10.1371/journal.pone.0281558.
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Mutations in BRAF exon 15 lead to conformational changes in its activation loops, resulting in constitutively active BRAF proteins which are implicated in the development of several human cancer types. Different BRAF inhibitors have been developed and introduced in clinical practice. Identification of BRAF mutations influences the clinical evaluation, treatment, progression and for that reason a sensitive and specific identification of BRAF mutations is on request from the clinic. Here we present the SensiScreen® FFPE BRAF qPCR Assay that uses a novel real-time PCR-based method for BRAF mutation detection based on PentaBases proprietary DNA analogue technology designed to work on standard real-time PCR instruments. The SensiScreen® FFPE BRAF qPCR Assay displays high sensitivity, specificity, fast and easy-to-use. The SensiScreen® FFPE BRAF qPCR Assay was validated on two different FFPE tumour biopsy cohorts, one cohort included malignant melanoma patients previously analyzed by the Cobas® 4800 BRAF V600 Mutation Test, and one cohort from colorectal cancer patients previously analyzed by mutant-enriched PCR and direct sequencing. All BRAF mutant malignant melanoma patients were confirmed with the SensiScreen® FFPE BRAF qPCR Assay and additional four new mutations in the malignant melanoma cohort were identified. All the previously identified BRAF mutations in the colorectal cancer patients were confirmed, and additional three new mutations not identified with direct sequencing were detected. Also, one new BRAF mutation not previously identified with ME-PCR was found. Furthermore, the SensiScreen® FFPE BRAF qPCR Assay identified the specific change in the amino acid. The SensiScreen® FFPE BRAF qPCR Assay will contribute to a more specific, time and cost saving approach to better identify and characterize mutations in patients affected by cancer, and consequently permits a better BRAF characterization that is fundamental for therapy decision.
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Stella, G., F. Rojas Llimpe, C. Barone, et al. "KRAS and BRAF mutational status as response biomarkers to cetuximab combination therapy in advanced gastric cancer patients." Journal of Clinical Oncology 27, no. 15_suppl (2009): e15503-e15503. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15503.
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e15503 Background: The prognosis of advanced gastric cancer (GC) patients (pt) is still poor despite the introduction of new chemotherapy regimens. In colorectal cancer (CRC) it has been demonstrated that KRAS or BRAF mutations are associated with resistance to treatment with the anti-EGFR mAbs. We have assessed whether, and to what extent, the mutational profile of KRAS and BRAF genes affects the response to cetuximab combination therapy in GC. Methods: We have collected 44 tumor samples from pts affected by locally advanced or metastatic GC undergoing cetuximab combination therapy as first-line treatment in two consecutive phase II studies. Thirteen pts received cetuximab plus FOLFIRI (FOLCETUX Study) and 31 pts cetuximab plus cisplatin and docetaxel (DOCETUX Study). Genomic DNA was extracted from paraffin-embedded tumor specimens from all cases. The mutational status of KRAS (exon 2) and BRAF (exon 15) was ascertained by PCR amplification followed by direct sequencing. The objective response was evaluated every 6 weeks by CT according to RECIST criteria. Results: KRAS and BRAF mutations were detected in 5 (11.4%) and 1 (2.3%), respectively, of the 44 tumors analyzed. These frequencies are consistent with those previously reported in GC. In the case of KRAS, 3 cases displayed amino acid substitutions of codon 12 and 1 of codon 13. One case had the A11V variant that had been reported in hematopoietic and lymphoid tissue of the stomach. The only BRAF mutation found in 1 sample was the classic V600E substitution. As a whole, 13.6 % of the analyzed tumors carried a mutation in either KRAS or BRAF genes. K-RAS and BRAF mutations were, as expected, mutually exclusive. In this pt cohort oncogenic activation of KRAS/BRAF-signaling pathways was not significantly associated to objective response (p= 0.757). Also, we found no correlation between KRAS/BRAF mutations and clinical outcome measured as overall survival. Conclusions: In advanced GC the frequency of mutations in KRAS and BRAF is lower as compared with CRC cancer. In our cases, the mutational status of KRAS and BRAF genes does not correlate with the response to cetuximab-based therapy in advanced gastric cancer patients. No significant financial relationships to disclose.
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Boulalas, Ioannis, Apostolos Zaravinos, Demetrios Delakas, and Demetrios A. Spandidos. "Mutational Analysis of the BRAF Gene in Transitional Cell Carcinoma of the Bladder." International Journal of Biological Markers 24, no. 1 (2009): 17–21. http://dx.doi.org/10.1177/172460080902400103.
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Purpose Mutational activation of the MAP kinase pathway is frequently found in many types of cancer. Recently, activating mutations in the BRAF gene, an important activator of this pathway, have been described in several tumor types including melanoma, colorectal and papillary thyroid cancer. The most frequent mutation in exon 15 (V600E) as well as several other mutations within exons 11 and 15 result in constitutive activation of the oncoprotein. Materials and methods Our study aimed to investigate BRAF mutations in 30 human bladder tumors and their adjacent normal tissues. The V600E mutation was screened by PCR/RFLP and exons 11, 14 and 15 of BRAF including intron-exon boundaries were sequenced. Results We detected two tumor specimens bearing two different mutations, both of which were found in exon 15. One sample showed the T1799A (V600E) and the other the G1798T (V600L) mutation. The first specimen was stage pT1a and grade II, whereas the second was stage pT2b and grade III. No mutations within the coding region of exons 11, 14, 15 and the intron-exon junctions for the remaining samples were found. Conclusions Our results suggest that involvement of BRAF mutations in the development of transitional cell carcinoma of the bladder is infrequent.
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Sullivan, Ryan J., and Keith T. Flaherty. "BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and Resistance." Journal of Skin Cancer 2011 (2011): 1–8. http://dx.doi.org/10.1155/2011/423239.
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Since the initial discovery that a subset of patients with cutaneous melanoma harbor BRAF mutations, substantial research has been focused on determining the pathologic consequences of BRAF mutations, optimizing diagnostic techniques to identify these mutations, and developing therapeutic interventions to inhibit the function of this target in mutation-bearing tumors. Recently, advances have been made which are revolutionizing the standard of care for patients with BRAF mutant melanoma. This paper provides an overview on the pathogenic ramifications of mutant BRAF signaling, the latest molecular testing methods to detect BRAF mutations, and the most recent clinical data of BRAF pathway inhibitors in patients with melanoma and BRAF mutations. Finally, emerging mechanisms of resistance to BRAF inhibitors and ways of overcoming this resistance are discussed.
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De Leo, Antonio, Daniela Serban, Thais Maloberti, et al. "Expanding the Spectrum of BRAF Non-V600E Mutations in Thyroid Nodules: Evidence-Based Data from a Tertiary Referral Centre." International Journal of Molecular Sciences 24, no. 4 (2023): 4057. http://dx.doi.org/10.3390/ijms24044057.
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The BRAF p.V600E mutation represents the most specific marker for papillary thyroid carcinoma and is potentially related to aggressive behavior and persistent disease. BRAF alterations other than the p.V600E are less common in thyroid carcinoma and represent an alternative mechanism of BRAF activation with unclear clinical significance. The study aims to describe the frequency and clinicopathologic characteristics of BRAF non-V600E mutations in a large cohort (1654 samples) of thyroid lesions characterized by next-generation sequencing. BRAF mutations have been found in 20.3% (337/1654) of thyroid nodules, including classic (p.V600E) mutation in 19.2% (317/1654) of samples and non-V600E variants in 1.1% of cases (19/1654). BRAF non-V600E alterations include 5 cases harboring p.K601E, 2 harboring p.V600K substitutions, 2 with a p.K601G variant, and 10 cases with other BRAF non-V600E alterations. BRAF non-V600E mutations have been reported in one case of follicular adenoma, three cases of conventional papillary thyroid carcinoma, eight cases of follicular variant of papillary carcinomas, one case of columnar cell variant papillary thyroid carcinoma, one case of oncocytic follicular carcinoma, and two bone metastasis of follicular thyroid carcinoma. We confirm that BRAF non-V600E mutations are uncommon and typically found in indolent follicular-patterned tumors. Indeed, we show that BRAF non-V600E mutations can be found in tumors with metastatic potential. However, in both aggressive cases, the BRAF mutations were concomitant with other molecular alterations, such as TERT promoter mutation.
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Bozzao, Cristina, Dora Varvara, Marilidia Piglionica, et al. "Survey of KRAS, BRAF and PIK3CA mutational status in 209 consecutive Italian colorectal cancer patients." International Journal of Biological Markers 27, no. 4 (2012): 366–74. http://dx.doi.org/10.5301/jbm.2012.9765.
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Molecular testing for KRAS and BRAF mutations in tumor tissue is a fundamental tool to identify patients with metastatic colorectal cancer (CRC) who are eligible for anti-EGFR monoclonal antibody therapy. We here report a molecular analysis by high-resolution melting analysis and direct sequencing of KRAS, BRAF and PIK3CA hot spot mutations in 209 Italian CRC patients. One hundred and ten patients (51%) were identified who were potentially nonresponders to anti-EGFR therapy: 90/209 patients (43%) harboring KRAS mutations, 13/117 (11.1%) with the V600E BRAF mutation, and 7/209 (3.3%) with mutations in PIK3CA exon 20. The prevalence of BRAF and PIK3CA mutations was significantly higher in patients older than 65 years (p=0.014 and p=0.018), while patients with triple-negative tumors were significantly younger than mutation carriers (p=0.000011). Patients with gene mutations also showed a trend towards preferential tumor location in the colon (p=0.026). Moreover, although involving a relatively small number of samples, we report the presence of a discordant mutational profile between primary tumors and secondary lesions (3/9 patients), suggesting that it is worthwhile to test other available tissues in order to better define the efficacy of targeted therapy. Further correlations of specific clinical features with tumor mutational profile could be helpful to predict the response of CRC patients to monoclonal antibody therapy.
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Margari, Niki, Abraham Pouliakis, Aris Spathis, et al. "Quality Control and Telemedicine for BRAF V600E Mutations in Papillary Thyroid Carcinomas." International Journal of Reliable and Quality E-Healthcare 4, no. 2 (2015): 12–30. http://dx.doi.org/10.4018/ijrqeh.2015040102.
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The assessment of BRAF V600E mutations is important for prognosis and treatment of Papillary Thyroid Carcinomas (PTC), the standard methods for their identification are molecular biology techniques. In this study, the potential of image morphometry applied to cell nuclei and sequentially the use of a Classification And Regression Tree (CART) is investigated, in order to: identify morphometric features useful to characterize BRAF mutations, and to eventually produce an algorithm identifying BRAF mutation status. The 140 studied cases had histological confirmation and known BRAF mutation status identified via real-time PCR. The analysis revealed that nuclear features contributing to BRAF mutation status identification via the CART model are related mostly to nuclear color. According to the results there is evidence that BRAF V600E mutations can be identified by measurable image features. Therefore, the proposed method is useful for quality control of BRAF V600E mutations on cytological slides, can serve as alternative to PCR method and may be used for remote assessment.
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George, Ben, Bradley W. Taylor, Matthew Lasowski, et al. "Prognostic effect of specific RAS/BRAF mutations in patients (pts) with metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 38, no. 15_suppl (2020): 4050. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.4050.
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4050 Background: Somatic mutations in KRAS, HRAS, NRAS (extended RAS) and BRAF have prognostic and predictive impact in pts with mCRC. We analyzed the prognostic impact of specific somatic mutations in extended RAS and BRAF. Methods: We retrospectively reviewed the electronic medical records of pts with mCRC at our institution who underwent comprehensive genomic profiling (CGP) utilizing the Foundation One assay. DNA was extracted from clinical specimens and CGP was performed on hybrid-capture, adaptor ligation-based libraries for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. BRAF mutations were classified as class I, II and III according to accepted nomenclature. Fisher’s exact test and Kaplan Meier estimates were used for statistical analyses. This project was approved by the Medical College of Wisconsin Institutional Review Board. Results: 273 pts were identified - median age at diagnosis was 57, 48% were male. Somatic mutations in extended RAS were found in 138 (50%) pts, majority being mutations in KRAS (46%). Among pts with KRAS mutations, codon 12, 13, 61 and 146 mutations accounted for 73%, 11%, 4% and 6% respectively while KRAS G12C mutations accounted for 9%. BRAF mutations were detected in 22 (8%) pts - BRAF V600E and non–V600E mutations accounting for 4.4% and 3.6% respectively. Among pts with BRAF mutations, 17 (77%) were kinase domain mutations, 16 of which could be further classified as class I (12/16), II (1/16) and III (3/16). Median overall survival (mOS) for the entire cohort was 26.4 months (mo). KRAS mutated pts had a mOS of 25.8 mo; pts with KRAS G12C mutation had a mOS of 23 mo compared to 27.1 mo for pts with other KRAS mutations (p < 0.001).Pts with BRAF mutation had a mOS of 26.2 mo; pts with BRAF V600E mutation had a mOS of 14.1 mo compared to 30.6 mo for pts with BRAF non-V600E mutations (p = 0.1). Conclusions: The poor prognosis of pts with KRAS G12C and BRAF V600E mutations compared to pts with other KRAS and BRAF mutations merit further biologic characterization with functional assays. Individualized therapeutic strategies must be conceptualized for mCRC pts with specific RAS/BRAF mutations, considering their widely disparate prognosis and putative downstream signaling mechanisms. Dynamic molecular simulation to understand conformational changes in proteins associated with specific mutations will be pivotal to optimizing precision therapeutic strategies.
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Kim, Min Jhi, Jin Kyong Kim, Gi Jeong Kim, et al. "TERT Promoter and BRAF V600E Mutations in Papillary Thyroid Cancer: A Single-Institution Experience in Korea." Cancers 14, no. 19 (2022): 4928. http://dx.doi.org/10.3390/cancers14194928.
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Telomerase reverse transcriptase (TERT) promoter mutation has been investigated for its clinical and prognostic significance in aggressive papillary thyroid cancer (PTC). In this study, we aimed to assess the prevalence, clinicopathologic features, and treatment outcomes of TERT mutation-positive PTCs along with the common BRAF V600E mutation. We performed mutational analyses for BRAF and the TERT promoter in thyroid cancer patients who had undergone surgery at our institution since 2019. We reviewed and analyzed 7797 patients with PTC in this study. The prevalence of BRAF V600E and TERT promoter mutations was 84.0% and 1.1%, respectively. Multifocal gene mutations in bilateral PTCs were identified. TERT promoter mutations were associated with older age, larger tumor size, tumor multifocality, tumor variants, advanced stages, more adjuvant radioactive iodine treatment (RAI), higher stimulated serum thyroglobulin level before RAI, and more uptakes in the regions outside the surgical field on a post-RAI whole-body scan. The coexistence of BRAF V600E and TERT promoter mutations exacerbated all clinicopathologic characteristics. The frequency of TERT promoter mutations was the lowest in this study, compared to previous studies. TERT promoter mutations consistently correlated with aggressive PTCs, and the synergistic effect of both mutations was evident. Specific clinical settings in our institution and in Korea may have led to these distinctive results. Prospective multicenter studies with longer follow-up periods are required to establish valuable oncologic outcomes.
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Rojo, Federico, Trinidad Caldes, Sandra Zazo, et al. "Prevalence of low-penetrance KRAS (codons 12/13 and 61) and BRAF mutations in metastatic colorectal carcinoma." Journal of Clinical Oncology 30, no. 15_suppl (2012): e14147-e14147. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14147.
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e14147 Background: In patients with metastatic colorectal cancer (mCRC), activating mutations within KRAS, which result in EGFR-independent intracellular signal transduction activation, are found in approximately 35-40% of patients with mCRC have been significantly associated with lack of response to cetuximab or panitumumab therapy. Although current guidelines recommend testing for frequent KRAS codons 12/13 mutations, emerging data indicate that additional KRAS and BRAF mutations are also predictive of non-responsiveness to anti-EGFR antibodies in mCRC. This study is aimed to analyze the prevalence of low-penetrance KRAS and BRAF V600 mutations in caucasian mCRC population. Methods: A two-institution retrospective cohort of 1,238 consecutive KRAS wild type mCRC patients previously studied for 7 mutations in codons 12/13 (G12D, G12A, G12V, G12S, G12R, G12C and G13D) by the CE-IVD marked ARMS-scorpion real-time polymerase chain reaction PCR (Therascreen, Qiagen) was assayed by the diagnostic TaqMelt PCR assay cobas KRAS mutation and cobas BRAF V600 mutation tests (Roche), which are designed to detect 19 mutations in KRAS codons 12, 13 and 61 (including G12F, G13C, G13R, G13S, G13A, G13V, G13I, Q61H, Q61K, Q61R, Q61L, Q61E and Q61P) and BRAF V600 (V600E, V600K and V600D) mutations. An additional cohort of 146 KRAS mutated patients by ARMS-scorpion PCR was studied. DNA was obtained by cobas DNA preparation kit from one single 5µm formalin-fixed paraffin-embedded tissue section. Results: In all samples, sufficient DNA was obtained for KRAS and BRAF mutational studies. Among 1238 KRAS codons 12/13 wild-type patients by ARMS-scorpion PCR,166 (13.4%) showed KRAS mutations, 117 (9.5%) in codons 12/13, and 49 (4%) in codon 61. BRAF V600 mutations were detected in 9% cases. In ARMS-scorpion PCR KRAS mutated patients, mutations were confirmed by cobas in all cases. Conclusions: The cobas mutation tests are robust and reproducible assays that, 1) detects a higher incidence (13.4%) of mutations in codons 12, 13, and 61 of the KRAS gene in wild-type mCRC population, 2) a relevant rate of BRAF mutations is present in the same population, and 3) requires a very small amount of tissue.
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Ozer, Erdener, Akin Sevinc, Dilek Ince, Resmiye Yuzuguldu, and Nur Olgun. "BRAF V600E Mutation: A Significant Biomarker for Prediction of Disease Relapse in Pediatric Langerhans Cell Histiocytosis." Pediatric and Developmental Pathology 22, no. 5 (2019): 449–55. http://dx.doi.org/10.1177/1093526619847859.
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Langerhans cell histiocytosis (LCH) is a rare disease presenting with usually a localized disease but sometimes a widespread aggressive disorder especially in children. Among the somatic mutations in RAF-MEK-ERK pathway, especially BRAF mutation has been detected so far in LCH. We aimed in this study to investigate the prognostic significance of the mutations of target genes playing a role in the RAF-MEK-ERK pathway in pediatric LCH. Mutation analyses were performed on tumor DNA extracted from formalin-fixed paraffin-embedded biopsy specimens of 38 pediatric LCH cases using a direct sequencing technique for BRAF, ARAF, MAP2K1, and MAP3K1 genes. The mutational status was correlated statistically with survival, clinical progression (disease relapse), and the established clinical prognostic parameters of LCH such as age, gender, localization, multisystem disease, central nervous system risk lesions, and risk organ or special-site involvement. BRAF V600E mutation was detected in 14 cases (36.8%), whereas ARAF mutation was found in only 1 case. No mutations were identified for MAP2K1 and MAP3K1 genes. The association of BRAF V600E mutation was significant in children with multisystem disease, younger age (<2 years), skin, and special organ involvement. BRAF V600E mutation was an independent predictive parameter for disease relapse. We therefore conclude that BRAF V600E mutation may be a significant marker for predicting disease progression in LCH and a candidate for targeted therapy for children with disease relapse and multisystem disease.
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Richtig, Georg, Ariane Aigelsreiter, Karl Kashofer, et al. "Two Case Reports of Rare BRAF Mutations in Exon 11 and Exon 15 with Discussion of Potential Treatment Options." Case Reports in Oncology 9, no. 3 (2016): 543–46. http://dx.doi.org/10.1159/000449125.
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BRAF mutations occur in up to 50% of melanomas. Mutations in the BRAF gene directly influence the patient’s treatment because several inhibitors are available that only target BRAFV600 mutations. Herein, we describe two cases of patients with metastatic melanomas, each carrying a ‘nonstandard’ mutation in the BRAF gene: BRAFK601E and BRAFG466E, respectively. The first patient was treated with a MEK inhibitor and the second one with ipilimumab. However, not all BRAF mutations result in increased BRAF kinase activity, and clinical data for ‘nonstandard’ mutations, such as those described in our case report, are sparse. Therefore, treatment with MEK inhibitors can be helpful in cases where BRAF mutations result in increased activity, whereas immune checkpoint inhibitors might be used in cases where the mutations lead to activity levels below those of the wild type.
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Lamy, A., E. Labourier, O. Prigneau, F. Di Fiore, R. Sesboüá, and J. Sabourin. "A method to assess KRAS/BRAF genotype in patients with metastatic colorectal cancer (mCRC) elligible for anti-EGFR therapies." Journal of Clinical Oncology 29, no. 4_suppl (2011): 383. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.383.
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383 Background: KRAS/BRAF mutation screening is a new diagnostic tool since activating mutations, especially for KRAS, are strong negative predictive factors for anti-EGFR monoclonal antibody therapies. Therefore, standardized, reliable, and rapid mutation detection methods are needed. The goal of the present study is to evaluate the concordance between a clinically validated laboratory-developed KRAS/BRAF SNaPshot test and a novel research use assay, the Signature KRAS/BRAF Mutations kit (Asuragen Inc.), in representative clinical specimens. Methods: Genomic DNA from FFPE mCRC specimens previously tested with the SNaPshot assay were analyzed using the Signature KRAS/BRAF mutations assay. The Signature assay consists of multiplex PCR followed by multiplex hybridization to fluorescent beads coupled to capture probes and detection on the Luminex analyzer. The qualitative assay detects 12 mutations in KRAS codons 12/13 and BRAF V600E based on the median fluorescence intensity (MFI) generated by each bead above (positive) or below (negative) a fixed cut off. Results: To date, KRAS/BRAF mutational status was successfully assessed with the signature assay in 248 samples. After initial testing, signature and SNaPshot assays were in qualitative agreement for 232 samples (93.5%): 166 positive for KRAS, 46 positive for BRAF, and 20 double negative. 16 samples (6%) presented discrepant results: (i) 11 false negative samples with fluorescence signals for the expected mutations above the average assay background signal but below the 450 MFI positive cut off preselected for this study (330-431 MFI), (ii) 3 samples positive for both KRAS and BRAF and (iii) 2 false positive samples. 7 discrepant samples have been retested to date resulting in an overall agreement of 99.6% (239/240). However, different KRAS mutations were identified by the SNaPshot and signature assays in 3 positive samples. Conclusions: The signature KRAS/BRAF mutations assay is an attractive method, easy to use, less time consuming than the SNaPshot assay, and potentially adaptable to routine clinical testing. Further analysis will establish and validate cut offs to be used in routine diagnostic procedures. No significant financial relationships to disclose.
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Padmanabhan, Chandrasekhar, Kimberly Brown Dahlman, Jordan Berlin, et al. "BRAF mutations in colonic high-grade neuroendocrine carcinoma." Journal of Clinical Oncology 34, no. 4_suppl (2016): 612. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.612.
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612 Background: The WHO 2010 has classified GI neuroendocrine neoplasms into well-differentiated neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). NEC is more aggressive than NET. Whole genome sequencing (WGS) has provided insight into the genetic underpinnings of NET but little is known about NEC. The aim of this study is to perform genomic profiling of NEC to better characterize the underlying mutations in this aggressive disease. Methods: We identified 9 patients who underwent biopsy or resection for NEC between 1/2005 - 6/2013 with histological blocks available. WGS was performed on DNA extracted from tissue from 2 patients with ≥80% tumor cellularity using the Illumina HiSeq 2500 platform. Validation and mutational analysis of the BRAF gene was performed on 2 WGS patients and an additional 7 patients via Sanger Sequencing of exon 11 and 15. Results: 7 of 9 patients (78%) presented with metastasis at initial diagnosis (Table). 8 patients died of disease within 25 months. In 2 NECs, we identified BRAF mutations on exon 15 by WGS. Patient S1 presented with cecal NEC and had an A1781G:p.D594G mutation on exon 15. Patient S2 presented with a descending colon NEC and had a c.1799T>A: p.V600E mutation on exon 15. An additional 7 colonic NECs were analyzed with Sanger Sequencing of exons 11 and 15. 2 had BRAFV600E mutations. Overall, BRAF mutations were present in 4 of 9 (44%) colonic NECs. The 3 cases with V600E mutations were large cell NECs, whereas the case with a D594G mutation was a small cell NEC. Conclusions: High grade colonic NEC is an aggressive tumor with high frequency (44%) of activating BRAF mutations. Further investigation is warranted to ascertain the incidence of BRAF mutations in a larger population as BRAF inhibition may be a potential avenue of targeted treatment for these patients. [Table: see text]
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Lowe, Kimberly, Lauren C. Bylsma, Elizabeth D. Levin-Sparenberg, Laura Sangaré, Jon Fryzek, and Dominik D. Alexander. "Prevalence of KRAS, NRAS, and BRAF gene mutations in metastatic colorectal cancer patients: A systematic literature review and meta-analysis." Journal of Clinical Oncology 37, no. 4_suppl (2019): 523. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.523.
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523 Background: A systematic literature review and meta-analysis was conducted to summarize the prevalence of KRAS, NRAS, and BRAF mutations in mCRC patients. These mutations have substantial implications for treatment decisions among mCRC patients. Methods: Multiple databases were searched to identify observational studies and clinical trials (standard of care arms only) that reported mutation status among mCRC patients. Random effects meta-analysis models were used to estimate summary prevalence estimates for each of the mutations. Subgroup and sensitivity analyses were conducted to identify potential sources of heterogeneity in mutation prevalence. Results: The meta-analyses included 275 studies comprising over 77,000 mCRC patients. The summary prevalence estimate was 35.9% for KRAS mutations, 7.1% for BRAF mutations, and 4.1% for NRAS mutations. Female patients had significantly more KRAS and BRAF mutations than males ( KRAS: 42.2% vs. 37.3%, p = 0.011; BRAF: 11.0% vs. 7.9%, p = 0.018), and significant variation by study location was observed for both KRAS (p = 0.025) and BRAF (p = 0.002) mutation prevalence. Conclusions: The prevalence of KRAS, BRAF, or NRAS mutations in mCRC patients varies significantly by gender and study location. compared to patients with wild-type tumors. The results of these analyses are informative for clinicians, patients, and researchers.
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Chimbangu, Clint Taonaishe, Li Xi, Zhou Ya, et al. "A literature review of a meta-analysis of BRAF mutations in non-small cell lung cancer." Medicine 103, no. 8 (2024): e34654. http://dx.doi.org/10.1097/md.0000000000034654.
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Background: The research on the relationship between the Braf Proto-oncogene (BRAF) mutation and lung cancer has generated conflicting findings. Nevertheless, there is an argument suggesting that assessing the BRAF status could offer benefits in terms of managing and prognosing individuals with non-small cell lung cancer (NSCLC). To present a comprehensive overview of this subject, we undertook an up-to-date meta-analysis of pertinent publications. Methods: We conducted an extensive literature search utilizing Medical Subject Headings keywords, namely “BRAF”, “mutation”, “lung”, “tumor”, “NSCLC”, and “neoplasm”, across multiple databases, including PubMed, EMBASE, ISI Science Citation Index, and CNKI. For each study, we calculated and evaluated the odds ratio and confidence interval, focusing on the consistency of the eligible research. Results: The meta-analysis unveiled a noteworthy correlation between BRAF mutation and lung cancer. No significant evidence was found regarding the connection between smoking and staging among individuals with BRAF mutations. Furthermore, a substantial disparity in the rate of BRAF mutations was observed between males and females. Conclusion: Our meta-analysis revealed a significant correlation between BRAF mutations and NSCLC. Moreover, we observed a higher incidence of BRAF lung mutations in females compared to males. Additionally, the BRAFV600E mutation was found to be more prevalent among female patients and nonsmokers.
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Zhang, Xuefei, Mo Li, Desheng Lv, et al. "Identification of a novel BRAF Thr599dup mutation in lung adenocarcinoma." Open Medicine 13, no. 1 (2018): 278–80. http://dx.doi.org/10.1515/med-2018-0042.
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AbstractBRAF mutations are known as oncogenic drivers of non-small cell lung cancer (NSCLC). BRAF inhibition has demonstrated anti-tumor activity in patients with BRAF V600E mutant NSCLC. Further molecular screening for novel BRAF thr599dup mutation is warranted. The novel BRAF Thr599dup gene mutation, for which the repeat amino acid-tyrosine is inserted between the 599th amino acid and the 600th amino acid in exon 15 of BRAF, was identified by next-generation sequencing (NGS) during routine clinical care in a lung carcinoma sample from an Asian never-smoker. Other putative driver alterations including EGFR, ALK were not found in that patient. BRAF Thr599dup gene mutation analysis was consistent with BRAF v600E gene mutation. Here we report a novel BRAF gene mutation with molecular characteristics consistent with those in BRAF-driven NSCLC. Our case expands the scope of BRAF gene mutations and provides broader molecular profiling for optimizing therapeutic options for patients with NSCLC. The new BRAF gene mutation has important clinical meaning for cancer patients.
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Stover, D. G., A. M. Cushman-Vokoun, C. L. Vnencak-Jones, and J. Berlin. "Analysis of BRAF and KRAS mutations in colorectal cancer and rectal carcinogenesis via fluorescent allele-specific PCR." Journal of Clinical Oncology 29, no. 4_suppl (2011): 436. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.436.
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436 Background: Molecular analysis has become increasingly relevant in the evaluation of colorectal carcinomas. Mutations in Ras-MAPK pathway proteins KRAS (present in 30-40% of colorectal cancer) and BRAF (10-14% of colorectal cancer) or mismatch repair (MMR) enzymes can impact response to therapy and/or can assist in defining hereditary predisposition. High frequency microsatellite instability (MSI) in colorectal cancer is associated with improved outcomes. Targeted therapies against BRAF and other components of the Ras-MAPK signaling pathway are becoming important aspects of treatment in colorectal and other cancers. Methods: A retrospective study was performed on 111 paraffin-embedded tumor specimens submitted between 1/07 and 3/09 for MSI testing based on family history and/or histologic features. DNA samples were screened for the BRAF V600E mutation and 7 KRAS mutations in codons 12 and 13 using fluorescent allele specific PCR with capillary electrophoresis. Clinical data was collected via chart review. Results: 58 males and 53 females were studied. The incidence of KRAS and BRAF mutations among the 111 samples was 49.5% and 6.3%, respectively. KRAS G12D and G12V were the most common mutations, representing 57% of total KRAS mutations. Dually positive KRAS and MSI tumors exclusively demonstrated G12D and G13D mutations. KRAS and BRAF mutations were mutually exclusive. Rectal cancers did not show evidence of BRAF V600E mutation (p=0.04). KRAS, BRAF, and MSI status did not correlate with survival, however pre-operative and post-operative carcinoembryonic antigen (CEA) levels were significantly associated with survival both in univariate and multivariate analyses. Conclusions: We demonstrate that BRAF V600E mutation is significantly associated with colon cancer and not rectal cancer, suggesting that BRAF mutations are not relevant in rectal carcinogenesis. Correlation between specific KRAS mutation and outcome may require larger populations. No significant financial relationships to disclose.
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Casula, Milena, Maria Colombino, Maria P. Satta, et al. "BRAF Gene Is Somatically Mutated but Does Not Make a Major Contribution to Malignant Melanoma Susceptibility: The Italian Melanoma Intergroup Study." Journal of Clinical Oncology 22, no. 2 (2004): 286–92. http://dx.doi.org/10.1200/jco.2004.07.112.
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Purpose Oncogenic activation of the BRAF gene has been demonstrated to be involved in the pathogenesis of malignant melanoma (MM). In this study, we investigated the contribution of BRAF to melanoma susceptibility, also making a comparison with frequency of CDKN2A germline mutations in MM patients from different areas in Italy. Patients and Methods Using a combination of denaturing high-performance liquid chromatography analysis and automated sequencing on genomic DNA from peripheral blood or tumor tissue samples, 569 MM patients (211 from northern Italy and 358 from southern Italy) were screened for BRAF mutations. Results Three BRAF germline sequence variants (M116R, V599E, and G608H) were identified in four (0.7%) of 569 MM patients. The most common BRAF mutation, V599E, was detected in one germline DNA sample only; M116R and G608H were newly described mutations. A high frequency (59%) of BRAF mutations was instead observed in tumor samples from patients also undergoing germline DNA analysis; at the somatic level, substitution of valine 599 was found to account for the majority (88%) of BRAF mutations. We then estimated the germline mutation rates in BRAF and CDKN2A among 358 consecutively collected patient samples originating in southern Italy; a low (2.5%) or very low (0.29%) prevalence of CDKN2A and BRAF mutations, respectively, was detected. Conclusion Mutation analysis of either blood DNA from a large collection of MM patients or matched MM tissues from a subset of such patients revealed that BRAF is somatically mutated and does not play a major role in melanoma susceptibility. The present study further suggests that patient origin may account for different mutation rates in candidate genes.
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Mayrhofer, Johanna E., Florian Enzler, Andreas Feichtner, et al. "Mutation-oriented profiling of autoinhibitory kinase conformations predicts RAF inhibitor efficacies." Proceedings of the National Academy of Sciences 117, no. 49 (2020): 31105–13. http://dx.doi.org/10.1073/pnas.2012150117.
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Kinase-targeted therapies have the potential to improve the survival of patients with cancer. However, the cancer-specific spectrum of kinase alterations exhibits distinct functional properties and requires mutation-oriented drug treatments. Besides post-translational modifications and diverse intermolecular interactions of kinases, it is the distinct disease mutation which reshapes full-length kinase conformations, affecting their activity. Oncokinase mutation profiles differ between cancer types, as it was shown for BRAF in melanoma and non–small-cell lung cancers. Here, we present the target-oriented application of a kinase conformation (KinCon) reporter platform for live-cell measurements of autoinhibitory kinase activity states. The bioluminescence-based KinCon biosensor allows the tracking of conformation dynamics of full-length kinases in intact cells and real time. We show that the most frequent BRAF cancer mutations affect kinase conformations and thus the engagement and efficacy of V600E-specific BRAF inhibitors (BRAFi). We illustrate that the patient mutation harboring KinCon reporters display differences in the effectiveness of the three clinically approved BRAFi vemurafenib, encorafenib, and dabrafenib and the preclinical paradox breaker PLX8394. We confirmed KinCon-based drug efficacy predictions for BRAF mutations other than V600E in proliferation assays using patient-derived lung cancer cell lines and by analyzing downstream kinase signaling. The systematic implementation of such conformation reporters will allow to accelerate the decision process for the mutation-oriented RAF-kinase cancer therapy. Moreover, we illustrate that the presented kinase reporter concept can be extended to other kinases which harbor patient mutations. Overall, KinCon profiling provides additional mechanistic insights into full-length kinase functions by reporting protein–protein interaction (PPI)-dependent, mutation-specific, and drug-driven changes of kinase activity conformations.
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Li, Wendong, Yanzhi Cui, Fei Yin, et al. "BRAF mutation in Chinese biliary tract cancer patients." Journal of Clinical Oncology 38, no. 15_suppl (2020): e16678-e16678. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16678.
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e16678 Background: Biliary tract cancers (BTCs) are a group of relatively rare invasive carcinomas including gallbladder carcinoma (GBC), intrahepatic (ICC), hilar (HCCA), and extrahepatic (ECC) cholangiocarcinoma. In the ROAR basket trial, dabrafenib, a BRAF inhibitor, combined with trametinib, a MEK inhibitor, demonstrated promising efficacy in patients with BTCs with an overall response rate (ORR) of 41% and a favorable safety profile. The frequency of BRAF mutations reported in BTC varies widely, and BRAF V600E mutations have been reported in 0% to 20% of BTCs. However, the frequencies of BRAF mutations in Chinese BTCs are not clear. Methods: A total of 926 BTC patients (203 ECC, 195 GBC, 59 HCCA, and 469 ICC) were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples from these patients were collected and sequenced using next-generation sequencing (NGS) targeting 450 cancer genes. Genomic alterations including single nucleotide variants, insertions and deletions, copy number variations, and fusions were assessed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: BRAF activating mutations were detected in 5.5% of Chinese BTC patients. There were 5.1% in ICC cases, 8.9% in ECC cases, 5.1% in HCCA cases, and 3.1% in GBC cases. BRAF V600E, the most common hotspot mutation, was detected in ICC and GBC with frequencies of 1.5% and 0.5%, respectively. No BRAF V600E was detected in ECC or HCCA. The top-ranked co-mutation genes with BRAF were TP53 (54%), ARID1A (40%), and SMAD4 (32%). Compared with BRAF wild-type cohort, the frequencies of ARID1A and SMAD4 mutations were significantly higher in patients with BRAF mutations cohort (40% vs 17%, P< 0.001; 32% vs 14%, P< 0.001), while KRAS mutations were mutually exclusive with BRAF mutations. Conclusions: To our knowledge, this is the largest BTCs cohort used to study the characterization of BRAF mutations in the Chinese patients. BRAF mutations occurred in 5.5% of patients, and BRAF V600E in 0.9%. These patients could benefit from treatment with a BRAF inhibitor combined with a MEK inhibitor. Analysis of BRAF V600E should be considered in patients with BTCs, especially in ICC and GBC. Clinical trial information: NCT03892577 .
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Abdelgadir, Omer, Yong-Fang Kuo, Anthony O. Okorodudu, M. Firoze Khan, Yu-Wei Cheng, and Jianli Dong. "KRAS, NRAS, and BRAF Hot-Spot Mutations in Relation to Sidedness of Primary Colorectal Cancer: A Retrospective Cohort Study." Diagnostics 15, no. 2 (2025): 142. https://doi.org/10.3390/diagnostics15020142.
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Background/Objective: Studies have shown an association between colorectal cancer (CRC) sidedness and gene mutations that may affect CRC clinical behavior. This study examined the association between specific KRAS, NRAS, and BRAF hot-spot mutations and primary CRC sidedness. Methods: We performed a retrospective cohort analysis of 722 patients diagnosed with primary CRC and tested for KRAS, NRAS, and BRAF hot-spot mutations at the University of Texas Medical Branch (UTMB) from January 2016 through July 2023. Multivariable logistic regressions analyses were conducted. Results:KRAS, NRAS, and BRAF hot-spot mutations rates were 37.8%, 4.6%, and 6.1%, respectively. Right-sided primary CRC had the highest prevalence of mutated tumors (64%). KRAS and BRAF hot-spot mutations were significantly different according to tumor sidedness. KRAS p.Gly12Asp, p.Gly12Val, and p.Gly13Asp showed a significantly increased likelihood of right-sided primary CRC compared to KRAS wildtype, 128%, 134%, and 221% higher, respectively. Conversely, KRAS p.Gly12Val and p.Gly13Asp mutations were associated with decreased likelihood of rectal cancer (53% lower) and left-sided tumors (56% lower), respectively. BRAF p.Val600Glu mutation, as opposed to BRAF wildtype, was associated with a 278% higher likelihood of right-sided CRC. No significant associations were observed between NRAS mutations and primary CRC sidedness. Conclusions: In primary CRC, specific mutations in KRAS (p.Gly12Asp, p.Gly12Val, and p.Gly13Asp) and BRAF p.Val600Glu were associated with increased likelihood of right-sided tumors. KRAS p.Gly12Val and p.Gly13Asp mutations were associated with decreased likelihood of rectal cancer and left-sided tumors, respectively. These findings suggest that tumorigenesis and mutational processes differ based on tumor sidedness. Further studies are needed to substantiate these findings.
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Baltruškevičienė, Edita, Ugnius Mickys, Tadas Žvirblis, Rokas Stulpinas, Teresė Pipirienė Želvienė, and Eduardas Aleknavičius. "Significance of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer patients receiving Bevacizumab: a single institution experience." Acta medica Lituanica 23, no. 1 (2016): 24–34. http://dx.doi.org/10.6001/actamedica.v23i1.3267.
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Background. KRAS mutation is an important predictive and prognostic factor for patients receiving anti-EGFR therapy. An expanded KRAS, NRAS, BRAF, PIK3CA mutation analysis provides additional prognostic information, but its role in predicting bevacizumab efficacy is unclear. The aim of our study was to evaluate the incidence of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer patients receiving first line oxaliplatin based chemotherapy with or without bevacizumab and to evaluate their prognostic and predictive significance. Methods. 55 patients with the first-time diagnosed CRC receiving FOLFOX ± bevacizumab were involved in the study. Tumour blocks were tested for KRAS mutations in exons 2, 3 and 4, NRAS mutations in exons 2, 3 and 4, BRAF mutation in exon 15 and PIK3CA mutations in exons 9 and 20. The association between mutations and clinico-pathological factors, treatment outcomes and survival was analyzed. Results. KRAS mutations were detected in 67.3% of the patients, BRAF in 1.8%, PIK3CA in 5.5% and there were no NRAS mutations. A significant association between the high CA 19–9 level and KRAS mutation was detected (mean CA 19–9 levels were 276 and 87 kIU/l, respectively, p = 0.019). There was a significantly higher response rate in the KRAS, NRAS, BRAF and PIK3CA wild type cohort receiving bevacizumab compared to any gene mutant type (100 and 60%, respectively, p = 0.030). The univariate Cox regression analysis did not confirm KRAS and other tested mutations as prognostic factors for PFS or OS. Conclusions. Our study revealed higher KRAS and lower NRAS, BRAF and PIK3CA mutation rates in the Lithuanian population than those reported in the literature. KRAS mutation was associated with the high CA 19–9 level and mucinous histology type, but did not show any predictive or prognostic significance. The expanded KRAS, NRAS, BRAF and PIK3CA mutation analysis provided additional significant predictive information.
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Rusinek, Dagmara, Aleksandra Pfeifer, Jolanta Krajewska, et al. "Coexistence of TERT Promoter Mutations and the BRAF V600E Alteration and Its Impact on Histopathological Features of Papillary Thyroid Carcinoma in a Selected Series of Polish Patients." International Journal of Molecular Sciences 19, no. 9 (2018): 2647. http://dx.doi.org/10.3390/ijms19092647.
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TERT promoter (TERTp) mutations are important factors in papillary thyroid carcinomas (PTCs). They are associated with tumor aggressiveness, recurrence, and disease-specific mortality and their use in risk stratification of PTC patients has been proposed. In this study we investigated the prevalence of TERTp mutations in a cohort of Polish patients with PTCs and the association of these mutations with histopathological factors, particularly in coexistence with the BRAF V600E mutation. A total of 189 consecutive PTC specimens with known BRAF mutational status were evaluated. TERTp mutations were detected in 8.5% of cases (16/189) with the C228T mutation being the most frequent. In six of the PTC specimens (3.2%), four additional TERTp alterations were found, which included one known polymorphism (rs2735943) and three previously unreported alterations. The association analysis revealed that the TERTp hotspot mutations were highly correlated with the presence of the BRAF V600E mutation and their coexistence was significantly associated with gender, advanced patient age, advanced disease stage, presence of lymph node metastases, larger tumor size, and tumor-capsule infiltration. While correlations were identified, the possibility of TERTp mutations being key molecular modulators responsible for PTC aggressiveness requires further studies.