BRAF Mutations In Patients Research Articles

Prospective Study to Assess the Clinicopathological and Prognostic Value of BRAF V600E Mutation in Metastatic Colorectal Cancer

Abstract Background BRAF is a protein kinase downstream of RAS in the RAS-RAF-MEK- ERK kinase pathway. The majority (>95%) of BRAF mutations in metastatic colorectal cancer (mCRC) is the BRAFV600E mutation, which is considered an important negative prognostic marker and is associated with resistance to standard chemotherapies in mCRC patients. Objectives This study aimed to investigate the BRAF mutation in patients with mCRC and its association with clinicopathological factors and survival outcomes. Patients and Methods The included specimens were analysed for BRAFV600E mutation by immunohistochemistry (IHC) from confirmed CRC patients with radiological or pathological evidence of metastasis. Results The BRAF mutation was positive in 9.1% of patients. Synchronous metastasis was observed in patients with BRAF mutation with statistical significance (P = 0.033). With regard to treatment, there was no statistically significant difference in patients with BRAF mutations who received targeted chemotherapy as first-line therapy also there was no statistically significant difference in median PFS of patients with BRAF mutation (p = 0.789) and also in median OS (p = 0.343). Conclusion Although the BRAF mutation is a relatively rare finding in mCRC, it is characterized by a critical negative impact on treatment outcome. Given this poor outcome, optimization of therapy is an important goal.

BRAF Mutations in Patients with Myeloid Neoplasms: A Cancer Center Multigene Next-Generation Sequencing Analysis Experience.

BRAF mutations are rare in myeloid neoplasms and are reported to be associated with poor treatment outcomes. The purpose of our study is to characterize BRAF mutations in myeloid neoplasms using a next-generation sequencing (NGS) panel based on the experiences of a single cancer center. We conducted a retrospective review of patients with myeloid neoplasms who underwent the HopeSeq studies between January 2018 and September 2023. A total of 14 patients with myeloid neoplasms carrying BRAF mutations were included in our cohort. The clinical, pathological, and molecular features of these patients were investigated. Our study indicates that BRAF mutations are rare in myeloid neoplasms, constituting only 0.53% (14/2632) of all myeloid neoplasm cases, with the most common BRAF mutation being BRAF V600E (4/14; 28.6%). Interestingly, we observed that six out of seven patients with acute myeloid leukemia (AML) exhibited AML with monocytic differentiation, and all the patients with AML exhibited an extremely poor prognosis compared to those without BRAF mutations. TET2 (5/14; 35.7%), ASXL1 (4/14; 28.6%), and JAK2 (4/14; 28.6%) were the three most frequently co-mutated genes in these patients. Moreover, we noted concurrent KMT2A gene rearrangement with BRAF mutations in three patients with AML (3/7; 42.9%). Our study suggests that although BRAF mutations are rare in myeloid neoplasms, they play a crucial role in the pathogenesis of specific AML subtypes. Furthermore, RAS pathway alterations, including BRAF mutations, are associated with KMT2A gene rearrangement in AML. However, these findings warrant further validation in larger studies.

Prevalence and Impact of BRAF mutation in patients with concomitant papillary thyroid carcinoma and Hashimoto's thyroiditis: a systematic review with meta-analysis.

Evidence suggests that patients with Hashimoto thyroiditis (HT) are at significantly higher risk of developing papillary thyroid cancer (PTC). However, the course of PTC in patients with both diseases concomitantly has been found to be more indolent than conventional PTC. Additionally, it has been well proven that BRAF mutation results in an aggressive course of PTC. The aims of this meta-analysis were to identify prevalence of BRAF mutation and its impact on clinicopathological features in patients with concomitant PTC-HT. Medline, Cochrane Library, Scopus, and Web of Science were searched until 16.09.2022, resulting in 227 articles, of which nine studies were included. Summary estimates, comparing patients with (A) BRAF (+) PTC-HT versus BRAF (+) PTC, and (B) BRAF (+) PTC-HT versus BRAF (-) PTC-HT, were generated with Review Manager 5.0. In total, 6395 patients were included in this review. PTC-HT patients had significantly less BRAF mutation than PTC patients (Odds Ratio (OR) (95% Confidence Interval (CI))=0.45 (0.35-0.58), P<0.001). BRAF (+) PTC-HT patients were significantly more likely to have multifocal lesions (OR (95% CI)=1.22 (1.04-1.44), P=0.01) but less likely to have lymph node metastasis (OR (95% CI)=0.65 (0.46-0.91), P=0.01) and extrathyroidal extension (OR (95% CI)=0.55 (0.32-0.96), P=0.03) compared to BRAF (+) PTC patients. BRAF (+) PTC-HT patients were more likely to have multifocal lesions (OR (95% CI)=0.71 (0.53-0.95), P=0.02), lymph node metastasis (OR (95% CI)=0.59 (0.44-0.78), P<0.001) and extrathyroidal extension (OR (95% CI)=0.72 (0.56-0.92), P=0.01) compared to BRAF (-) PTC-HT patients. This meta-analysis highlights that the lower prevalence of BRAF mutation in patients with PTC-HT than conventional PTC may explain the indolent clinicopathological course in this cohort.

Predicting the BRAF mutation with pretreatment MRI radiomics features for melanoma brain metastases receiving Gamma Knife radiosurgery

To develop a model using radiomics features extracted from magnetic resonance imaging (MRI) images of Gamma Knife radiosurgery (GKRS) to predict the BRAF mutation in patients with melanoma brain metastases (MBM). Data of 220 tumours were classified into two groups. One was a group whose BRAF mutation was identified, and the other group whose BRAF mutation was not identified. We extracted 1,962 radiomics features from gadolinium contrast-enhanced T1-weighted MRI treatment-planning images. Synthetic Minority Over-sampling TEchnique (SMOTE) was performed to address the unbalanced data-related issues. A single-layer neural network (NN) was used to build predictive models with radiomics features. The sensitivity, specificity, accuracy, and the area under the curve (AUC) were evaluated to assess the model performance. The prediction performance for the final evaluation without the SMOTE had an accuracy of 77.14%, a specificity of 82.44%, a sensitivity of 81.85%, and an AUC of 0.79. The application of SMOTE improved the prediction model to an accuracy of 83.1%, a specificity of 87.07%, a sensitivity of 78.82%, and an AUC of 0.82. The current study showed the feasibility of generating a highly accurate NN model for the BRAF mutation prediction. The prediction performance improved with SMOTE. The model assists physicians to obtain more accurate expectations of the treatment outcome without a genetic test.

Evaluation of BRAF Mutations in Patients with Colorectal Cancer in the East of Iran

Background: Several genetic alterations in cell growth regulatory genes, such as BRAF, are associated with colorectal cancer. Due to the introduction of biological agents designed to treat cancer, diagnostic tests using nucleic acids extracted from formalin-fixed and paraffin-embedded tissues are becoming more common. Objective: This study aimed to determine the incidence of BRAF mutations in colorectal cancer patients. Materials and Methods: 50 paraffin-embedded cancer specimens were obtained from Imam Reza Hospital of Birjand in Iran. PCR was used to amplify and sequence the BRAF gene exon 15, which was extracted from paraffin-embedded tissue using an improved technique. Results: 2/43 (4%) of patients with colorectal cancer exhibited the BEAF V600E mutation. Most of the mutations occurred in patients over 50 years of age. Conclusion: To understand how genetics and environment interact to influence the low incidence of BRAF mutations in the east of Iran, further research is needed to determine what is driving this low incidence of BRAF mutations and what factors contribute to it.

Abstract 4205: Profiling symptom burden of RAS and BRAF mutations in patients with colorectal cancer: Results from the ColoCare Study

Abstract Background: Colorectal cancer (CRC) is a complex and heterogeneous disease characterized by distinct molecular features such as RAS and BRAF mutations. Assessing these molecular aberrations provides clinical guidance for selecting and predicting response with therapeutic modalities. Few reports have suggested that patient symptom burden at diagnosis differs across molecular subtypes of CRC. However, the association of RAS and BRAF mutations and symptom burden post-diagnosis in CRC patients has yet to be examined in a prospective cohort. Methods: We assessed CRC patients, stage I-IV, enrolled in the Moffitt ColoCare Study site with clinical molecular testing results and who completed a six-month questionnaire. Tumor mutation (MT) status (RAS/BRAF/Wildtype (WT)) was abstracted from the medical record. The MD Anderson Symptom Inventory (MDASI) was used to assess the severity of 13 cancer-related symptoms on a 1-to-10 scale. Mean scores in mutation subgroups were compared with one-way ANOVA. Linear regression analysis evaluated the association between symptom burden and mutation status. Multivariable regression models were adjusted for age, sex, stage at diagnosis, treatment, and microsatellite instability (MSI). Results: Among the 158 patients, the mean age at diagnosis was 60.9 ± 11.58 years. The prevalence of RAS and BRAF mutations was 30.4% (N=48) and 6.3% (N=10), respectively. Statistically significant mean differences between the mutation subgroups were distress (p=0.005), difficulty remembering (p=0.015), lack of appetite (p=0.042), and sadness (p=0.007). Patients with a BRAF-MT reported significantly more distress (p=0.001), difficulty remembering (p=0.029), and sadness (p=0.002) at six months compared to RAS-MT or RAS/BRAF-WT. Patients with a RAS-MT reported an increased lack of appetite (p=0.038) compared to BRAF-MT or RAS/BRAF-WT. Patients with a BRAF-MT reported higher severity of symptoms interfering with the enjoyment of life (p&amp;lt;0.001), work (p=0.005), and mood (p&amp;lt;0.001) compared to RAS-MT or RAS/BRAF-WT. In an adjusted multivariable model, patients with BRAF-MT tumors reported significantly greater distress compared with RAS/BRAF-WT patients [β = 3.18 per unit increase in severity, 95% CI (1.30 - 5.07), p=0.001)]. Overall symptom burden was associated with greater interference with daily activities for BRAF-MT patients when compared to RAS/BRAF-WT patients [β = 2.95, 95% CI (1.42 - 4.48), p&amp;lt;0.001)]. Conclusions: Tumors with BRAF-MT are molecularly classified into the serrated pathway, which has distinct clinical characteristics and risk factor profile. In this study, patients with tumors harboring BRAF-MT reported a higher symptom burden six months post-diagnosis than those with RAS-MT or RAS/BRAF-WT tumors. While the prevalence of BRAF-MT was low in this population, these findings warrant further investigation in a larger cohort. Citation Format: Gazelle Rouhani, Amanda M. Bloomer, Maria F. Gomez, Gillian K. Trujillo, Devon N. Conant, Seth I. Felder, Cornelia M. Ulrich, Christopher I. Li, Jane C. Figueiredo, Adetunji T. Toriola, Biljana Gigic, Martin Schneider, David Shibata, Erin M. Siegel. Profiling symptom burden of RAS and BRAF mutations in patients with colorectal cancer: Results from the ColoCare Study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4205.

Addressing the unmet needs of patients with BRAF-mutated melanoma in Latin America: Expert perspective.

Melanoma represents an increasing public health burden with extensive unmet needs in Latin America (LA). A mutation in the BRAF gene is present in approximately 50% of all melanomas in White populations and is a target of precision medicine, with the potential to dramatically improve patient outcomes. Thus, increased access to BRAF testing and therapy is LA must be explored. At a multi-day conference, a panel of Latin American experts in oncology and dermatology were provided with questions to address the barriers limiting access to testing for BRAF mutation in patients with melanoma in LA, who may be eligible for targeted therapy to improve their prognosis. During the conference, responses were discussed and edited until a consensus on addressing the barriers was achieved. Identified challenges included ignorance of BRAF-status implications, limited human and infrastructural resources, affordability and reimbursement, fragmented care delivery, pitfalls in the sample journey, and lack of local data. Despite the clear benefits of targeted therapies for BRAF-mutated melanoma in other regions, there is no clear path to prepare LA for a sustainable personalized medicine approach to this disease. Due to melanoma's time-sensitive nature, LA must aim to provide early access to BRAF testing and consider mutational status within treatment decision making. To this end, recommendations are provided and include establishing multidisciplinary teams and melanoma referral centers and improving access to diagnosis and treatment.

49P Treatment management in RAS and BRAF mutations in patients with metastatic colorectal cancer

49P Treatment management in RAS and BRAF mutations in patients with metastatic colorectal cancer

Evaluation of Ki-67 staining index and BRAF mutation in women diagnosed with advanced endometriosis

Introduction: Recent studies have proposed that advanced endometriosis might harbor histopathological, molecular, and genetic properties of malignant lesion. Thus we aimed to investigate the presence of Ki-67 staining index (KSI) and BRAF mutation in patients with and without recurrent endometriosis of stage III and IV. Materials and methods: Cross sectional study on 50 consecutive patients with endometriosis of stage III and IV was performed. Tissue specimens collected during laparoscopic surgery were used for the evaluation of presence of KSI and BRAF mutation. Also, serum levels of tumor markers including CA-125, CA19-9, AMH and αFP were gathered. Results: The mean ± SD of KSI was 12.18 ± 16.58. Forty-one out of 50 (82%) patients had a non-recurrent disease. KSI ⩾ 10% was found in 20 patients (40%). Furthermore, 29 patients (58%) and 13 patients (26%) had high levels of CA-125 and CA19-9, respectively. No evidence of significant correlation was observed between the KSI and CA-125 and CA19-9 (all p values &gt; 0.05). However, a positive correlation was observed between CA-125 and CA19-9 ( r = 0.55, p-value = 0.02). KSI level was insignificantly lower in recurrent patients compared with non-recurrent patients (9.78 ± 6.24 vs 12.71 ± 18.09, p-value = 0.33). Other tumor markers did not show any statistically significant difference (all p values &gt; 0.05). None of the participants had BRAF V600E mutation. Conclusion: Endometriosis manifests malignant behavioral of rapid proliferation but the exact genetic alteration causing this phenomenon is not understood.

The clinicopathological features of ganglioglioma with CD34 expression and BRAF mutation in patients with epilepsy.

The aim of the study was to evaluate the clinicopathological features, as well as the surgical prognosis, of epilepsy-associated gangliogliomas (GG) with CD34 expression and BRAFV600E mutation. Clinical data of patients who underwent epilepsy surgery for GG were retrospectively studied. Univariate and multivariate analyses were performed to evaluate the correlations of clinical and pathological factors with molecular markers of CD34 expression and BRAFV600E mutation in GG. A total of 208 patients with GG had immunohistochemical detection of CD34 expression (positive/negative: 184/24), and among them, 89 patients had immunohistochemical detection of BRAFV600E mutation (positive/negative: 54/35). By univariate and multivariate analyses, seizure aura (p = 0.025), concordance of ictal electroencephalogram (EEG) findings (p = 0.045) and medial temporal tumor (p = 0.030) were found to be related to CD34 expression, but only hospitalization time (p = 0.042) was different for BRAF-mutated status. In addition, drug-resistant epilepsy (p = 0.040) and concordance of interictal EEG findings (p = 0.009) were found to be associated with tumor progression-free survival (PFS) in univariate analysis, but only concordance of interictal EEG findings was with significance in multivariate analysis. However, CD34 expression or BRAFV600E mutation in GG was not found to be associated with surgical outcomes of seizure control and tumor PFS. The CD34 expression or BRAFV600E mutation in GG may partly influence the distribution of clinicopathological features of patients with epilepsy, but they may be not able to predict the surgical prognosis of seizure outcome and tumor recurrence.

Pathogenic BRAF mutations in prostate cancer: Frequency and distribution.

257 Background: Human cancers are known to harbor mutations in BRAF, a rare but clinically significant finding. BRAF p. V600E is the most common hot spot mutation and has been well described, however other activating mutations are less well studied. Herein we evaluate the landscape of BRAF pathogenic/likely pathogenic (P/LP) variations in prostate cancer patients. Methods: De-identified records from patients with primary prostate cancer who underwent NGS with Tempus xF (ctDNA, 105 genes) or xT (tissue, DNAseq of 648 genes, 500× coverage, full transcriptome RNAseq for a subset of patients) were analyzed from a real-world dataset. Results: There were 5,902 patients identified with prostate cancer who underwent any Tempus xT testing, of whom 85 (1.4%) harbored a P/LP BRAF mutation. Of these 85 patients, the most prevalent BRAF mutation identified was BRAF K601E (Lys601Glu) (36% of total), followed by Gly469Ala (18%) and Leu597Arg (8%, Table) There were 4,177 patients identified with primary prostate cancer who underwent any Tempus xF testing, of whom 50 (1.2%) harbored a P/LP BRAF mutation. Similarly, the most prevalent BRAF mutation identified was BRAF K601E (26%). Conclusions: This study presents the first large-scale genomic characterization of BRAF mutations in patients with prostate cancer using both tissue and ctDNA NGS analysis. Among thousands of samples from prostate cancer patients, K601E was the most common BRAF mutation. This confirms findings of smaller studies and has implications for developmental therapeutics. Further studies should document the natural history of BRAF K601E in prostate cancer. [Table: see text]

Prevalence and patterns of mutations in RAS/RAF/MEK/ERK/MAPK signaling pathway in colorectal cancer in North Africa

BackgroundOur review discuss (i) the findings from analyzed data that have examined KRAS, NRAS and BRAF mutations in patients with colorectal cancer (CRC) in North Africa and to compare its prevalence with that shown in other populations and (ii) the possible role of dietary and lifestyle factors with CRC risk. MethodsUsing electronic databases, a systematic literature search was performed for the KRAS, NRAS, and BRAF mutations in CRC patients from Morocco, Tunisia, Algeria and Lybia. ResultsSeventeen studies were identified through electronic searches with six studies conducted in Morocco, eight in Tunisia, two in Algeria, and one in Libya. A total of 1843 CRC patients were included 576 (31.3%) in Morocco, 641 (34.8%) in Tunisia, 592 (32.1%) in Algeria, and 34 (1.8%) in Libya. Overall, the average age of patients was 52.7 years old. Patients were predominantly male (56.6%). The mutation rates of KRAS, NRAS and BRAF were 46.4%, 3.2% and 3.5% of all patients, respectively. A broad range of reported KRAS mutation frequencies have been reported in North Africa countries. The KRAS mutation frequency was 23.9% to 51% in Morocco, 23.1% to 68.2% in Tunisia, 31.4% to 50% in Algeria, and 38.2% in Libya. The G12D was the most frequently identified KRAS exon 2 mutations (31.6%), followed by G12V (25.4%), G13D (15.5%), G12C (10.2%), G12A (6.9%), and G12S (6.4%). G12R, G13V, G13C and G13R are less than 5%. There are important differences among North Africa countries. In Morocco and Tunisia, there is a higher prevalence of G12D mutation in KRAS exon 2 (≈50%). The most frequently mutation type in KRAS exon 3 was Q61L (40%). A59T and Q61E mutations were also found. In KRAS exon 4, the most common mutation was A146T (50%), followed by K117N (33.3%), A146P (8.3%) and A146V (8.3%).ConclusionKRAS mutated CRC patients in North Africa have been identified with incidence closer to the European figures. Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology. This approach may be able to significantly reduce the burden of CRC in North Africa.

The analysis and validation of the prediction value of conventional and contrast-enhanced ultrasonography for BRAF mutant papillary thyroid microcarcinoma

BRAF has certain potential in distinguishing aggressive papillary thyroid microcarcinoma (PTMC). However, it is not recommended to conduct BRAF analysis for all suspicious thyroid nodules <1 cm. In order to investigate the ultrasound value indicating BRAF mutation among PTMC, which showed discrepancy in previous studies, we aimed to establish a predictive model based on conventional and contrast-enhanced ultrasonography. We consecutively and retrospectively enrolled patients with PTMC who underwent fine-needle aspiration biopsy (FNAB) at our hospital between January 2020 and January 2021. All PTMC patients received conventional and contrast-enhanced ultrasound prior to FNAB, samples gained went through cytological analysis and BRAF testing subsequently. The following conventional ultrasonography data were analyzed: maximum diameter, echogenicity, echo homogeneity, echogenic foci, location, shape, boundary, aspect ratio, and blood flow volume. Moreover, the following contrast-enhanced ultrasonography data were also analyzed: degree, homogeneity, completeness, and enhancement method. Time-intensity curves from contrast-enhanced ultrasonography were analyzed using VueBox software for different regions of interest, including the entire tumor, the area of strongest enhancement, and healthy thyroid glands. The independent risk factors for BRAF mutation in PTMC were identified using univariate and multivariate logistic regression. Their predictive value was tested through internal validation. Of the 103 PTMC lesions analyzed, 72 involved BRAF mutations. Five independent ultrasonographic risk factors for BRAF mutation were identified: relative time to peak value in the area of strongest enhancement, unclear boundary, location adjacent to thyroid capsules, maximum diameter >0.5 cm, and punctate echogenic foci. A predictive model based on these factors was able to diagnose BRAF mutations in PTMC, with an area under the curve (AUC) of 0.824. During internal validation, this model showed an AUC of 0.723. Conventional and contrast-enhanced ultrasound characteristics, including relative time to peak value in the area of strongest enhancement, unclear boundary, location adjacent to thyroid capsules, maximum diameter >0.5 cm, and punctate echogenic foci, may be useful for predicting BRAF mutations in patients with PTMC.

Nomogram based on radiomics analysis of ultrasound images can improve preoperative BRAF mutation diagnosis for papillary thyroid microcarcinoma.

BackgroundThe preoperative identification of BRAF mutation could assist to make appropriate treatment strategies for patients with papillary thyroid microcarcinoma (PTMC). This study aimed to establish an ultrasound (US) radiomics nomogram for the assessment of BRAF status.MethodsA total of 328 PTMC patients at the China-Japan Friendship Hospital between February 2019 and November 2021 were enrolled in this study. They were randomly divided into training (n = 232) and validation (n = 96) cohorts. Radiomics features were extracted from the US images. The least absolute shrinkage and selection operator (LASSO) regression was applied to select the BRAF status-related features and calculate the radiomics score (Rad-score). Univariate and multivariate logistic regression analyses were subsequently performed to identify the independent factors among Rad-score and conventional US features. The US radiomics nomogram was established and its predictive performance was evaluated via discrimination, calibration, and clinical usefulness in the training and validation sets.ResultsMultivariate analysis indicated that the Rad-score, composition, and aspect ratio were independent predictive factors of BRAF status. The US radiomics nomogram which incorporated the three variables showed good calibration. The discrimination of the US radiomics nomogram showed better discriminative ability than the conventional US model both in the training set (AUC 0.685 vs. 0.592) and validation set (AUC 0.651 vs. 0.622). Decision curve analysis indicated the superior clinical applicability of the nomogram compared to the conventional US model.ConclusionsThe US radiomics nomogram displayed better performance than the conventional US model in predicting BRAF mutation in patients with PTMC.

KRAS and BRAF Mutations in Patients with Hepatocellular Carcinoma in Senegal

Hepatocellular carcinoma (HCC) is a public health problem in developing countries where chronic HBV is endemic. The objective of our study was to determine the prevalence of KRAS and BRAF mutations in patients with HCC. Mutations in codons 12 and 13 of KRAS and the V600E mutation of the BRAF gene were searched by HRM on Light Cycler 480 and confirmed by direct sequencing. A total of 34 HCC patients underwent molecular testing for codon 12 and 13 mutations in the KRAS gene and the V600E mutation in the BRAF gene. Melting curve analysis showed a prevalence of 23.5% (n=8/34) for the KRAS gene and 41.2% (n=14/34) for the BRAF gene. The mean age of BRAF mutation carriers was lower compared with KRAS mutation carriers. Chronic HBV carriage appeared to play a role in the development of these mutations, increasing the risk by 2 (CI(95)=0.55-7.24; p=0.395) for BRAF and by 1.78 (CI(95)=0.23-13.5; p=1) for KRAS. KRAS and BRAF mutations do not appear to play a role in tumor metastasis. However, these results need to be confirmed by further studies with a larger sample size. Alterations in the RAS/RAF/MAP Kinase pathway appear to be more prominent in HBV-induced HCC. This may hinder management with receptor tyrosine kinase inhibitors, the basis for treatment of advanced HCC.

BRAF V600E Positive Hairy Plasma Cell Leukemia; Are the Cytoplasmic Projections in Plasma Cells Predictive of a Particular Molecular Characterization?

Introduction: Plasma cell leukemia (PCL) is a rare and clinically aggressive form of plasma cell dyscrasia. Despite the significant role of BRAF mutation in plasma cell neoplasms, this mutation has been rarely considered in these cases. Finding evidence guiding us toward assessing the BRAF mutation in patients with plasma cell neoplasms could help make the suitable decision for targeted therapy. Case Presentation: A 79-year-old man presented with leukocytosis. Peripheral blood smear exhibited marked lymphocytosis and infiltration of about 50% abnormal lymphoid cells with slender cell-surface projections and oval shape nucleus. These findings raised the provisional diagnosis of hairy cell leukemia (HCL) or HCL variants (HCL-v). Molecular analysis confirmed the presence of BRAFV600E mutation, which was in agreement with HCL diagnosis, albeit the flow cytometric assessment of abnormal lymphocytes corroborated PCL. Conclusions: Together with the previous comprehensive analysis regarding the association of cytoplasmic projections and BRAF mutations, our findings could suggest this morphological characteristic in plasma cells (PCs) as an indication for the assessment of BRAF V600E mutation in PC dyscrasias.

BRAF Mutations and Inflammatory Gene Expression in Myeloma Cells from Patients with Renal Dysfunction

BRAF Mutations and Inflammatory Gene Expression in Myeloma Cells from Patients with Renal Dysfunction

USP8, USP48, and BRAF mutations differ in their genotype-phenotype correlation in Asian Indian patients with Cushing's disease.

To estimate the prevalence of USP8, USP48, and BRAF mutations in patients with Cushing's disease (CD) from the Indian subcontinent, and determine their genotype-phenotype correlation. We prospectively recruited 46 patients with CD who underwent surgery between September 2015 and July 2019 at our institute. Fresh frozen tumour tissue was obtained in all patients. Using Sanger sequencing, the presence of somatic USP8 mutations was documented and the frequency of USP48 and BRAF mutations in USP8 wild-type corticotroph adenomas was determined. Clinical, hormonal, and surgical data were then compared between USP8-, USP48- and BRAF-variant carriers and patients with wild-type tumours. Signature USP8 mutations were detected in 17 (37%) patients. Of the 29 USP8 wild-type adenomas, 4 (13.8%) harboured USP48 mutations, one of them being a splice-site mutation that has previously not been described. BRAF mutations were not found in any of the 29 patients. Corticotroph adenomas with USP8 mutations had a higher incidence of Crooke's hyaline change than wild-type tumours (70.6 vs. 37.9%, p = 0.032). Adenomas with USP48 mutations had a higher rate of cavernous sinus invasion than their wild-type counterparts (50 vs. 4%, p = 0.042). No other significant phenotypic difference could be established between mutant and wild-type tumours. The prevalence of USP8 mutations in our series of patients with CD was 37%. The prevalence of USP48 mutations in USP8 wild-type adenomas was 13.8%, including a novel splice-site mutation. BRAF mutations were not found in any USP8 wild-type tumour. USP8-mutants showed significantly more Crooke's hyaline change and USP48-mutants were more likely to demonstrate cavernous sinus invasion.

Population-based analysis of the prevalence of BRAF mutation in patients diagnosed with cutaneous melanoma and its significance as a prognostic factor.

The prevalence of BRAF mutation has been reported in between 38% and 48% of melanoma patients, based on mainly Stage III or metastatic melanoma, however, information based on population-based studies is scarce. We performed a population-based retrospective cohort study to determine the prevalence of the BRAF mutation in patients diagnosed with in situ and infiltrating cutaneous malignant melanoma in the province of Girona between 2009 and 2011. Using the database of the Girona Cancer Registry, we performed BRAF mutation analysis based on paraffin-embedded tissue. This data was then correlated with other known clinical and histological prognostic factors for survival. We found 286 incident cases of cutaneous melanoma in the Girona Cancer Registry database. Excluding missing cases, BRAF-mutated patients constituted 38.9% of "in situ" melanoma cases and 53.8% of invasive melanoma cases. Five-year relative survival was not statistically different between BRAF-mutated patients (93.6%; 95%CI: 87.1-100.5) and non-mutated patients (84.3%, 95%CI: 75.3-94.8). Only stage was significant as a prognostic factor for survival based on multivariate analysis. From our population-based study, we conclude that BRAF mutation is not an independent prognostic factor for melanoma survival.

Frequency and Clinicopathological Profile Associated with Braf Mutations in Patients with Advanced Melanoma in Spain

Real-world data on BRAF mutation frequency in advanced melanoma are lacking in Spain. Moreover, data available on clinicopathological profile of patients with advanced BRAF-mutant melanoma are currently limited. This study aimed to assess the frequency of BRAF V600 mutations in Spanish patients with advanced or metastatic melanoma and to identify clinical and histopathological features associated with BRAF-mutated tumors. A multicenter, cross-sectional epidemiological study was conducted in 33 Spanish hospitals in adult patients with stage IIIc/IV melanoma. A total of 264 patients were included. The median age was 68 years and 57% were male. Melanoma mainly involved skin with intermittent (40.4%) and low or no sun exposure (43.5%). Most patients (85.6%) had stage IV disease (M1a: 19.3%; M1b: 13.3%; M1c: 22.7%). Serum lactate dehydrogenase levels were elevated in 20% of patients. Superficial spreading melanoma was the most frequent histological type (29.9%). Samples were predominantly obtained from metastases (62.7%), mostly from skin and soft tissues (80%). BRAF mutation analysis was primarily performed using the Cobas 4800 BRAF V600 Mutation Test (92.8%) on formalin-fixed, paraffin-embedded tissue (95.8%). BRAF mutations were detected in 41.3% of samples. Multivariate analysis identified age (odd ratio [OR] 0.975) and stage IV M1a (OR 2.716) as independent factors associated with BRAF mutation. The frequency of BRAF mutations in tumor samples from patients with advanced or metastatic melanoma in Spain was 41.3%. BRAF mutations seem to be more frequent in younger patients and stage M1a patients.This study provides the basis for further investigation regarding BRAF-mutated advanced melanoma in larger cohorts.