Abstract
Erdheim-Chester disease (ECD) is a rare histiocytic disorder that is challenging to diagnose and treat. We performed molecular analysis of BRAF in the largest cohort of ECD patients studied to date followed by N/KRAS, PIK3CA, and AKT1 mutational analysis in BRAF wild-type patients. Forty-six of 80 (57.5%) of patients were BRAFV600E-mutant. NRAS mutations were detected in 3 of 17 ECD BRAFV600E wild-type patients. PIK3CA mutations (p.E542K, p.E545K, p.A1046T, and p.H1047R) were detected in 7 of 55 patients, 4 of whom also had BRAF mutations. Mutant NRAS was present in peripheral blood CD14(+) cells, but not lymphoid cells, from an NRASQ61R mutant patient. Our results underscore the central role of RAS-RAF-MEK-ERK activation in ECD and identify an important role of activation of RAS-PI3K-AKT signaling in ECD. These results provide a rationale for targeting mutant RAS or PI3K/AKT/mTOR signaling in the subset of ECD patients with NRAS or PIK3CA mutations.
© 2014 by The American Society of Hematology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Class I Phosphatidylinositol 3-Kinases
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Erdheim-Chester Disease / genetics*
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Erdheim-Chester Disease / metabolism
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Female
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GTP Phosphohydrolases / genetics*
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GTP Phosphohydrolases / metabolism
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Histiocytes / metabolism
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Humans
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MAP Kinase Signaling System / genetics
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Male
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Middle Aged
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Phosphatidylinositol 3-Kinases / genetics*
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Phosphatidylinositol 3-Kinases / metabolism
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Point Mutation
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins p21(ras)
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Recurrence
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ras Proteins / genetics
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ras Proteins / metabolism
Substances
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KRAS protein, human
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Membrane Proteins
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Proto-Oncogene Proteins
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Phosphatidylinositol 3-Kinases
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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GTP Phosphohydrolases
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NRAS protein, human
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Proto-Oncogene Proteins p21(ras)
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ras Proteins