High prevalence of somatic MAP2K1 mutations in BRAF V600E–negative Langerhans cell histiocytosis

Brown, Noah A.; Furtado, Larissa V.; Betz, Bryan L.; Kiel, Mark J.; Weigelin, Helmut C.; Lim, Megan S.; Elenitoba-Johnson, Kojo S.J.

doi:10.1182/blood-2014-05-577361

Cited by 335 publications

(240 citation statements)

References 20 publications

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“…Similar small in-frame deletions within exon 2 of MAP2K1 were recently reported in most Langerhans cell histiocytosis cases lacking BRAF p.V600E mutation, where it functions as an alternate mechanism of MAP kinase pathway activation. 21,22 Given the unresectable nature of this patient's tumor and medically refractory seizures, targeted therapy with the MEK inhibitor trametinib is being considered.…”

Section: Neurooncologymentioning

confidence: 99%

Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy

Kline

Joseph

Grenert

et al. 2016

NEUONC

177

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Background. Molecular profiling is revolutionizing cancer diagnostics and leading to personalized therapeutic approaches. Herein we describe our clinical experience performing targeted sequencing for 31 pediatric neurooncology patients. Methods. We sequenced 510 cancer-associated genes from tumor and peripheral blood to identify germline and somatic mutations, structural variants, and copy number changes. Results. Genomic profiling was performed on 31 patients with tumors including 11 high-grade gliomas, 8 medulloblastomas, 6 low-grade gliomas, 1 embryonal tumor with multilayered rosettes, 1 pineoblastoma, 1 uveal ganglioneuroma, 1 choroid plexus carcinoma, 1 chordoma, and 1 high-grade neuroepithelial tumor. In 25 cases (81%), results impacted patient management by: (i) clarifying diagnosis, (ii) identifying pathogenic germline mutations, or (iii) detecting potentially targetable alterations. The pathologic diagnosis was amended after genomic profiling for 6 patients (19%), including a high-grade glioma to pilocytic astrocytoma, medulloblastoma to pineoblastoma, ependymoma to high-grade glioma, and medulloblastoma to CNS high-grade neuroepithelial tumor with BCOR alteration. Multiple patients had pathogenic germline mutations, many of which were previously unsuspected. Potentially targetable alterations were identified in 19 patients (61%). Additionally, novel likely pathogenic alterations were identified in 3 cases: an in-frame RAF1 fusion in a BRAF wild-type pleomorphic xanthoastrocytoma, an inactivating ASXL1 mutation in a histone H3

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Section: Neurooncologymentioning

confidence: 99%

Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy

Kline

Joseph

Grenert

et al. 2016

NEUONC

177

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“…The proliferating Langerhans cells have abundant,oftenvacuolatedcytoplasmandvesicularnucleicontaininglineargroovesorfolds.Thepresence ofBirbeckgranulesinthecytoplasmischaracteristic.BRAFV600Emutationswerefoundin38%to 57% of LCH cases. MAP2K1 mutation is another knownmutation [9]. [7,8].…”

Section: Discussionmentioning

confidence: 99%

Puzzle histiocytosis (solitary mononuclear xanthogranuloma with LCH component). A case report*

Woszczyna-Mleczko¹,

Kowalik²,

Harazin-Lechowska³

et al. 2016

pjp

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“…Targeted sequencing studies identified MAP2K1 mutations in 15%-50% of cases with wild-type BRAF (Figure 2). 20,21 Another WES study of 3 LCH cases revealed 1 lesion with BRAF-V600E, 1 with a complex somatic activating mutation in ARAF, and 1 without MAPK gene mutations identified. As in our series, Nelson et al also described a very low overall rate of somatic mutations.…”

Section: Molecular Landscape Of Lch: Mapk Activationmentioning

confidence: 99%

Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders

Allen

Parsons

2015

Hematology

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High prevalence of somatic MAP2K1 mutations in BRAF V600E–negative Langerhans cell histiocytosis

Abstract: • Targeted

Cited by 335 publications

References 20 publications

Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy

Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy

Puzzle histiocytosis (solitary mononuclear xanthogranuloma with LCH component). A case report*

Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders

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