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Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes
Lynn H. Lee, … , Nicolas N. Nassar, Ashish R. Kumar
Lynn H. Lee, … , Nicolas N. Nassar, Ashish R. Kumar
Published February 9, 2017
Citation Information: JCI Insight. 2017;2(3):e89473. https://doi.org/10.1172/jci.insight.89473.
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Clinical Medicine Oncology

Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes

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Abstract

Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing. Fifteen patients (21%) carried the known BRAF V600E mutation, and 11 patients (15%) carried various mutations in MAP2K1, which we confirm induce constitutive activation of extracellular signal–regulated kinase (ERK) and were sensitive to inhibitors of mitogen-activated protein kinase kinase (MEK, the product of MAP2K1). We also identified recurring ALK rearrangements, and 4 LCH patients with an uncommon in-frame deletion in BRAF (N486_P490del or N486_T491>K), resulting in constitutive activation of ERK with resistance to V600E-specific inhibitors. We subsequently describe clinical cases where patients with aggressive multisystem LCH experience dramatic and sustained responses to monotherapy with either dabrafenib or trametinib. These findings support our conclusion that comprehensive genomic profiling should be regularly applied to these disorders at diagnosis, and can positively impact clinical care.

Authors

Lynn H. Lee, Anjelika Gasilina, Jayeeta Roychoudhury, Jason Clark, Francis X. McCormack, Joseph Pressey, Michael S. Grimley, Robert Lorsbach, Siraj Ali, Mark Bailey, Philip Stephens, Jeffrey S. Ross, Vincent A. Miller, Nicolas N. Nassar, Ashish R. Kumar

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Figure 1

Comutation plot demonstrating the variety of likely pathogenic mutations and gene fusions detected through targeted sequencing.

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Comutation plot demonstrating the variety of likely pathogenic mutations...
Single columns represent individual patients with the diagnosis identified in the first row. Samples are grouped by disease type and age group as indicated in horizontal bars. Asterisks at the bottom represent 2 previously reported patients as described in the text. Basic plot created using cBioPortal (39, 40).

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