Recurrent BRAF mutations in Langerhans cell histiocytosis

Badalian-Very, Gayane; Vergilio, Jo‐Anne; Degar, Barbara; MacConaill, Laura E.; Brandner, Barbara; Calicchio, Monica L.; Kuo, Frank C.; Ligon, Azra H.; Stevenson, Kristen E.; Kehoe, Sarah M.; Garraway, Levi A.; Hahn, William C.; Meyerson, Matthew; Fleming, Mark D.; Rollins, Barrett J.

doi:10.1182/blood-2010-04-279083

Cited by 1,015 publications

(926 citation statements)

References 19 publications

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“…Inhibition of BRAF activation by vemurafenib improves the survival of patients with metastatic melanomas carrying the BRAFV600E mutation [51]. BRAFV600E mutations were reported in patients with LCH in 2010 [52], and we therefore screened patients with other types of histiocytosis for this mutation. We used pyrosequencing to test DNA, from paraffin-embedded samples from 127 patients with histiocytoses, for BRAFV600 mutations, and reassessed histology findings [53••].…”

Section: Braf Inhibition As An Alternative To Ifnα For Ecd Patients Cmentioning

confidence: 99%

Erdheim–Chester Disease

et al. 2014

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Erdheim-Chester disease (ECD) is a rare (approximately 500 known cases worldwide), non-inherited, nonLangerhans form of histiocytosis of unknown origin, first described in 1930. It is characterized by xanthomatous or xanthogranulomatous infiltration of tissues by foamy histiocytes, "lipid-laden" macrophages, or histiocytes, surrounded by fibrosis. Diagnosis of ECD involves the analysis of histiocytes in tissue biopsies: these are typically foamy and CD68+ CD1a− in ECD, whereas in Langerhans cell histiocytosis (LCH) they are CD68+ CD1a+. 99 Technetium bone scintigraphy revealing nearly constant tracer uptake by the long bones is highly suggestive of ECD, and a "hairy kidney" appearance on abdominal CT scan is observed in approximately half of ECD cases. Central nervous system involvement is a strong prognostic factor and an independent predictor of death in cases of ECD. Optimum initial therapy for ECD seems to be administration of interferon α (or pegylated interferon α), and prolonged treatment significantly improves survival; however, tolerance may be poor. Cases of ECD present with strong systemic immune activation, involving IFNα, IL-1/IL1-RA, IL-6, IL-12, and MCP-1, consistent with the systemic immune Th-1-oriented disturbance associated with the disease. More than half of ECD patients carry the BRAF V600E mutation, an activating mutation of the protooncogene BRAF. A small number of patients harboring this mutation and with severe multisystemic and refractory ECD have been treated with vemurafenib, a BRAF inhibitor, which was proved very beneficial.

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Section: Braf Inhibition As An Alternative To Ifnα For Ecd Patients Cmentioning

confidence: 99%

Erdheim–Chester Disease

et al. 2014

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“…8 Young individuals with LC histiocytosis are reportedly more commonly positive for BRAF V600E. 8 The two patients tested in this study were of advanced age (69 and 80 years of age). All of the leukemias in this study were of ambiguous lineage or acute myeloid leukemia that expressed T-cell antigens.…”

Section: Discussionmentioning

confidence: 83%

“…FISH was performed on a lymph node of one patient who had a trisomy 21 leukemic clone. As BRAF mutations occur in a significant percentage of LC histiocytosis, 8 BRAF V600E testing was performed in three cases by real-time polymerase chain reaction (RT-PCR). DNA was extracted from formalin-fixed, paraffin-embedded tissue (two cases) or B5-fixed tissue (one case) using the DNeasy blood and tissue kit, and then diluted to a DNA concentration of 66.7 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

Langerhans cell histiocytosis in acute leukemias of ambiguous or myeloid lineage in adult patients: support for a possible clonal relationship

et al. 2014

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Four patients presented with acute leukemia of ambiguous or myeloid lineage in association with Langerhans cell histiocytosis and provide evidence suggesting a common origin of the two neoplasms. One patient had a non-constitutional trisomy 21 in both the leukemic blasts and the Langerhans cells indicative of a clonal relationship. A second case expressed CD2, CD13, and CD117 on both the Langerhans cells and the blasts suggesting a possible clonal relationship. All four cases exhibited geographic intermingling of the Langerhans cell histiocytosis and acute leukemia and shared unique features including extramedullary leukemia involving lymph nodes in all cases with Langerhans cell histiocytosis only present in sites involved by acute leukemia. T-cell antigen expression was present in all cases with one meeting criteria for mixed phenotype acute leukemia, T/myeloid, not otherwise specified. These findings support the concept that coexistent Langerhans cell histiocytosis and acute leukemia is clonally related in some cases. Furthermore, these cases of acute myeloid or acute leukemia of ambiguous lineage with Langerhans cell histiocytosis share some unique features suggesting a common underlying neoplastic hematopoietic stem cell.

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“…However, recent studies have highlighted the role of the RAS/RAF/ERK (MAPK) pathway in the pathogenesis of several histiocytic disorders, although few cases of RDD have been evaluated [5][6][7][8][9]31]. The RAS/RAF/ERK (MAPK) pathway is involved in various cellular functions including cellular proliferation, differentiation, and migration; mutation of genes involved in this pathway has been implicated in oncogenesis [32].…”

Section: Discussionmentioning

confidence: 99%

“…The etiology of RDD is very poorly understood. Recent studies have shown frequent BRAF V600E mutations in Langerhans cell histiocytosis (LCH) [5,6], Erdheim-Chester disease (ECD) [7], histiocytic sarcoma [8], and follicular dendritic cell sarcoma [8]. Further, NRAS, KRAS, and PIK3CA activating mutations have also been shown in ECD [6,9], highlighting the emerging importance of the RAF/MEK/ERK pathway in some histiocytic disorders.…”

Section: Introductionmentioning

confidence: 99%

Rosai–Dorfman Disease Harboring an Activating KRAS K117N Missense Mutation

Shanmugam

Margolskee

Kluk

et al. 2016

Head and Neck Pathol

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Rosai-Dorfman disease (RDD) or sinus histiocytosis with massive lymphadenopathy is a rare histiocytic proliferation that is generally considered to be reactive with a benign clinical course. The etiology of RDD is very poorly understood. Recent studies have shown frequent BRAF, NRAS, KRAS, and PIK3CA activating mutations in several histiocytic neoplasms highlighting the emerging importance of the RAF/MEK/ERK pathway in the pathogenesis of these diseases. Here we report a case of Rosai-Dorfman disease involving the submandibular salivary gland with a KRAS K117N missense mutation discovered by next-generation sequencing. These results suggest that at least a subset of RDD cases may be clonal processes. Further mutational studies on this rare histiocytic disease should be undertaken to better characterize its pathogenesis as well as open up potential avenues for therapy.

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Recurrent BRAF mutations in Langerhans cell histiocytosis

Abstract: Langerhans cell histiocytosis (LCH) has

Cited by 1,015 publications

References 19 publications

Erdheim–Chester Disease

Erdheim–Chester Disease

Langerhans cell histiocytosis in acute leukemias of ambiguous or myeloid lineage in adult patients: support for a possible clonal relationship

Rosai–Dorfman Disease Harboring an Activating KRAS K117N Missense Mutation

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