scholarly journals BRAF Fusions in Histiocytic Disorders: Frequency and Clinical Characteristics

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2582-2582
Author(s):  
Saurabh Zanwar ◽  
Jithma P. Abeykoon ◽  
Aldo A. Acosta-Medina ◽  
Aishwarya Ravindran ◽  
Karen Rech ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Clinical Characteristics ◽  
Advisory Board ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Juvenile Xanthogranuloma ◽  
Study Cohort ◽  
Gene Fusions ◽  
Braf Gene

Abstract Background: Activation of extracellular-signal regulated kinase (ERK) is almost universal in histiocytic disorders and is driven by genomic alterations in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases (PI3K) pathways. While BRAFV600E mutations are well described in histiocytic disorders, less is known about BRAF fusions. The goal of our study is to describe the frequency and clinical characteristics of patients harboring BRAF fusions. Methods: We included patients with a diagnosis of histiocytic disorder seen at our institution from November 2016-June 2021. Only those who had adequate BRAF testing were included. The following were considered adequate BRAF testing: 1) unequivocally positive BRAF V600E immunostain with or without molecular confirmation; 2) successful multigene next generation sequencing (mostly Tempus â or FoundationOne â) if BRAF V600Eimmunostain was equivocal or negative. We also searched the literature for similar cases and compared BRAF fusions found in histiocytic disorders to those found in solid tumors and other hematologic conditions. Results: One hundred and twenty-six patients were included in this study. BRAF fusions were detected in 7 (6%) patients. The median follow-up for these patients was 1.4 years (95% CI: 0.4-not reached). The frequency according to disease subtypes is as follows: Erdheim-Chester disease (ECD; 2/46 [4%]), Langerhans cell histiocytosis (LCH; 1/41 [2%]), adult or juvenile xanthogranuloma (AXG/JXG; 4/7 [57%]), and histiocytic or Langerhans cell sarcoma (HS/LCS; 0/9 [0%]). The median age at diagnosis for our study cohort was 34 years (range, 7-81 years) and 5 were females. The clinical characteristics and nature of BRAF fusions of our 7 patients plus additional 13 cases from the literature are shown in Table 1. For the final cohort of 20 patients with BRAF-fusions, the median age was 16 years (range, 0.5-81 years) and most (56%) were females. The distribution by histiocytic subtypes is as follows: AXG/JXG (45%), LCH (40%), ECD (10%), HS/LCS (5%). Two patients received cobimetinib as frontline treatment in our cohort and achieved partial responses. Of these two patients, one completed 12 cycles (12 months) of cobimetinib and had a sustained PR while the other patient received 2 cycles before having to hold therapy due to intolerable adverse effects despite dose reduction. From literature review, another patient (LR-12) received cobimetinib as second line treatment and achieved complete response. We found 15 unique BRAF gene fusions with 4 being recurrent. Except for AGAP3-BRAF, none of these BRAF fusions in histiocytosis has been reported in solid tumors or hematologic conditions to date. Conclusions: BRAF gene fusions occur rarely (<5%) in histiocytic disorders. The only exception is AXG/JXG where more than half of the patients harbor BRAF gene fusions. These gene fusions are mostly distinct to histiocytosis and not found in solid tumors or other hematologic conditions. Figure 1 Figure 1. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board.

scholarly journals Novel BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers

2020 ◽  
Author(s):  
Payal Jain ◽  
Lea F. Surrey ◽  
Joshua Straka ◽  
Pierre Russo ◽  
Richard Womer ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Fusion Partner ◽  
Gene Fusions ◽  
Braf Gene ◽  
Mitogen Activated Protein ◽  
Hematopoietic Disorders ◽  
Mechanistic Basis

Pediatric histiocytic neoplasms are clonal hematopoietic disorders driven by mutations activating the mitogen-activated protein kinase (MAPK) pathway, such as BRAF-V600E. In non-BRAFV600E cases, we investigated alternative MAPK mutations and found two novel BRAF gene fusions. We investigated the distinct responsiveness of novel BRAF fusions to RAFi therapies and explored the mechanistic basis of such differential responses compared to other BRAF fusions. Two histiocytic patient tumors were analyzed using the CHOP Comprehensive Next-Gen Sequencing Solid Tumor Panel and a targeted RNA-seq panel for 106 fusion partner genes. In the two M- and L-type histiocytic neoplasms assessed, we found novel and rare BRAF gene fusions, MTAP-BRAF and MS4A6A-BRAF, respectively. Both BRAF fusions activated the MAPK/ PI3K pathways and showed homo- and hetero-dimerization with BRAF and the respective N-terminal fusion partner. In contrast to common BRAF fusions, MTAP-BRAF and MS4A6A-BRAF did not respond to PLX8394 due to a lack of disruption of active fusion homo- and hetero-dimers, which was in turn due to the untargeted, stable dimerization mediated by the N-terminal fusion partners. Conversely, we observed robust suppression with LY3009120 that bound fusion dimers and kept them in an inactivate confirmation. MEKi were found to successfully suppress fusion driven signaling and oncogenic phenotypes. Our finding that PLX8394 does not disrupt MTAP-BRAF or MS4A6A-BRAF dimerization due to contribution of N-terminal partners defines a novel paradigm for the distinct mechanisms sought by BRAF fusions in response to RAFi therapy. Overall, this study highlights the unique and differential biology hijacked by BRAF fusions in response to RAFi and further warrants detailed mechanistic classification of BRAF fusions based on their responsiveness to targeted agents.

scholarly journals High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2700-2703 ◽  
Author(s):  
Julien Haroche ◽  
Frédéric Charlotte ◽  
Laurent Arnaud ◽  
Andreas von Deimling ◽  
Zofia Hélias-Rodzewicz ◽  
...  
Keyword(s):  
Unknown Origin ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Juvenile Xanthogranuloma ◽  
Braf Mutations ◽  
Dendritic Cell Sarcoma ◽  
Erdheim Chester Disease ◽  
Rosai Dorfman Disease ◽  
Erdheim Chester ◽  
Chester Disease

Abstract Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAF mutations have been observed in Langerhans cell histiocytosis (LCH). We investigated the frequency of BRAF mutations in several types of histiocytoses. Histology from 127 patients with histiocytoses were reviewed. Detection of BRAFV600 mutations was performed by pyrosequencing of DNA extracted from paraffin embedded samples. Diagnoses of Erdheim-Chester disease (ECD), LCH, Rosai-Dorfman disease, juvenile xanthogranuloma, histiocytic sarcoma, xanthoma disseminatum, interdigitating dendritic cell sarcoma, and necrobiotic xanthogranuloma were performed in 46, 39, 23, 12, 3, 2, 1, and 1 patients, respectively. BRAF status was obtained in 93 cases. BRAFV600E mutations were detected in 13 of 24 (54%) ECD, 11 of 29 (38%) LCH, and none of the other histiocytoses. Four patients with ECD died of disease. The high frequency of BRAFV600E in LCH and ECD suggests a common origin of these diseases. Treatment with vemurafenib should be investigated in patients with malignant BRAFV600E histiocytosis.

scholarly journals The distribution of BRAF gene fusions in solid tumors and response to targeted therapy

2015 ◽  
Vol 138 (4) ◽  
pp. 881-890 ◽  
Author(s):  
Jeffrey S. Ross ◽  
Kai Wang ◽  
Juliann Chmielecki ◽  
Laurie Gay ◽  
Adrienne Johnson ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Solid Tumors ◽  
Gene Fusions ◽  
Braf Gene

scholarly journals Recurrent BRAF mutations in Langerhans cell histiocytosis

Blood ◽  
2010 ◽  
Vol 116 (11) ◽  
pp. 1919-1923 ◽  
Author(s):  
Gayane Badalian-Very ◽  
Jo-Anne Vergilio ◽  
Barbara A. Degar ◽  
Laura E. MacConaill ◽  
Barbara Brandner ◽  
...  
Keyword(s):  
Langerhans Cells ◽  
Langerhans Cell Histiocytosis ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Neoplastic Disease ◽  
Braf Mutations ◽  
Multiple Organs ◽  
Mitogen Activated Protein ◽  
Formalin Fixed Paraffin Embedded

Abstract Langerhans cell histiocytosis (LCH) has a broad spectrum of clinical behaviors; some cases are self-limited, whereas others involve multiple organs and cause significant mortality. Although Langerhans cells in LCH are clonal, their benign morphology and their lack (to date) of reported recurrent genomic abnormalities have suggested that LCH may not be a neoplasm. Here, using 2 orthogonal technologies for detecting cancer-associated mutations in formalin-fixed, paraffin-embedded material, we identified the oncogenic BRAF V600E mutation in 35 of 61 archived specimens (57%). TP53 and MET mutations were also observed in one sample each. BRAF V600E tended to appear in younger patients but was not associated with disease site or stage. Langerhans cells stained for phospho-mitogen–activated protein kinase kinase (phospho-MEK) and phospho-extracellular signal-regulated kinase (phospho-ERK) regardless of mutation status. High prevalence, recurrent BRAF mutations in LCH indicate that it is a neoplastic disease that may respond to RAF pathway inhibitors.

scholarly journals Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis

Blood ◽  
2016 ◽  
Vol 128 (21) ◽  
pp. 2533-2537 ◽  
Author(s):  
Rikhia Chakraborty ◽  
Thomas M. Burke ◽  
Oliver A. Hampton ◽  
Daniel J. Zinn ◽  
Karen Phaik Har Lim ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Gene Fusion ◽  
Mapk Pathway ◽  
Langerhans Cell ◽  
Model Systems ◽  
Braf V600e ◽  
Braf Gene ◽  
Erk Activation ◽  
Key Points ◽  
Genetic Mechanisms

Key Points A BRAF gene fusion and small in-frame BRAF deletions were found in a subset of LCH lesions lacking BRAF-V600E or MAP2K1 mutations. In LCH model systems, responses to MAPK pathway inhibitors depend on the specific genetic alteration that drives ERK activation.

scholarly journals BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers

2020 ◽  
Author(s):  
Payal Jain ◽  
Lea Surrey ◽  
Joshua Straka ◽  
Richard Womer ◽  
Marilyn Li ◽  
...  
Keyword(s):  
Braf V600e Mutation ◽  
Braf V600e ◽  
Gene Fusions ◽  
Braf Inhibitors ◽  
Braf Gene ◽  
Mek Inhibition ◽  
Hematopoietic Disorders ◽  
Stable Fusion

Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.

BRAF V600E expression in juvenile xanthogranuloma occurring after Langerhans cell histiocytosis

2018 ◽  
Vol 180 (4) ◽  
pp. 933-934 ◽  
Author(s):  
F. Bellinato ◽  
M. Maurelli ◽  
C. Colato ◽  
R. Balter ◽  
G. Girolomoni ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Juvenile Xanthogranuloma

scholarly journals Three decades of progress from surgery to medical therapy for isolated neuroaxis BRAF V600E–positive Langerhans cell histiocytosis management: illustrative case

2021 ◽  
Vol 1 (19) ◽  
Author(s):  
Nallammai Muthiah ◽  
Kamil W. Nowicki ◽  
Jennifer L. Picarsic ◽  
Michael P. D’Angelo ◽  
Daniel F. Marker ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Mapk Pathway ◽  
Clinical Manifestations ◽  
Tumor Burden ◽  
Langerhans Cell ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Illustrative Case ◽  
Surgical Interventions ◽  
Mitogen Activated Protein

BACKGROUND “Langerhans cell histiocytosis” (LCH) is a term that encompasses single-system or multisystem disorders traditionally characterized by a proliferation of clonal CD1a+/CD207+ myeloid-derived histiocytes. In most cases of LCH, mitogen-activated protein kinase (MAPK) pathway somatic mutations lead to near universal upregulation of phosphorylated extracellular signal-regulated kinase expression. The clinical manifestations of LCH are numerous, but bone involvement is common. Intracranial lesions, especially as isolated manifestations, are rare. OBSERVATIONS The authors presented the case of a long-term survivor of exclusive intracranial LCH that manifested with isolated craniofacial bone and intraparenchymal central nervous system recurrences, which were managed with 3 decades of multimodal therapy. The patient was initially diagnosed with LCH at age 2 years, and the authors documented the manifestations of disease and treatment for 36 years. Most of the patient’s treatment course occurred before the discovery of BRAF V600E. Treatments initially consisted of chemotherapy, radiosurgery, and open resections for granulomatous LCH lesions. Into young adulthood, the patient had a minimal disease burden but still required additional radiosurgical procedures and open resections. LESSONS Surgical treatments alleviated the patient’s immediate symptoms and allowed for tumor burden control. However, surgical interventions did not cure the underlying, aggressive disease. In the current era, access to systemic MAPK inhibitor therapy for histiocytic lesions may offer improved outcomes.

scholarly journals Frequency detection of BRAF V600E mutation in a cohort of pediatric langerhans cell histiocytosis patients by next-generation sequencing

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Shunqiao Feng ◽  
Lin Han ◽  
Mei Yue ◽  
Dixiao Zhong ◽  
Jing Cao ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Langerhans Cell Histiocytosis ◽  
Mutation Screening ◽  
Langerhans Cell ◽  
Braf V600e ◽  
P Value ◽  
Type I ◽  
Next Generation ◽  
Mutation Status ◽  
Generation Sequencing

Abstract Background Langerhans cell histiocytosis (LCH) is a rare neoplastic disease that occurs in both children and adults, and BRAF V600E is detected in up to 64% of the patients. Several studies have discussed the associations between BRAF V600E mutation and clinicopathological manifestations, but no clear conclusions have been drawn regarding the clinical significance of the mutation in pediatric patients. Results We retrieved the clinical information for 148 pediatric LCH patients and investigated the BRAF V600E mutation using next-generation sequencing alone or with droplet digital PCR. The overall positive rate of BRAF V600E was 60/148 (41%). The type of sample (peripheral blood and formalin-fixed paraffin-embedded tissue) used for testing was significantly associated with the BRAF V600E mutation status (p-value = 0.000 and 0.000). The risk of recurrence declined in patients who received targeted therapy (p-value = 0.006; hazard ratio 0.164, 95%CI: 0.046 to 0.583). However, no correlation was found between the BRAF V600E status and gender, age, stage, specific organ affected, TP53 mutation status, masses close to the lesion or recurrence. Conclusions This is the largest pediatric LCH study conducted with a Chinese population to date. BRAF V600E in LCH may occur less in East Asian populations than in other ethnic groups, regardless of age. Biopsy tissue is a more sensitive sample for BRAF mutation screening because not all of circulating DNA is tumoral. Approaches with low limit of detection or high sensitivity are recommended for mutation screening to avoid type I and II errors.

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