Next-generation sequencing and whole-exome sequencing (WES) studies detected 35 common mutations, as well as mutations unique to B-ALL (16) and HS (15), including BRAFD594G.
Our study detected several BRAF mutations in histiocytic sarcomas, which may be important in understanding the tumorigenesis of this rare neoplasm and providing mechanisms for potential therapeutical opportunities.
We also provide follow-up regarding a previously published case of histiocytic sarcoma with IGH/BCL2 fusion gene in which the patient subsequently developed follicular lymphoma and, later, diffuse large B-cell lymphoma.
Immunoglobulin gene rearrangement studies showed a clonal rearrangement of the IGH gene in both HS and DLBCL with identical amplicons, suggesting a shared origin of the neoplastic clones.
We performed a molecular characterization of HS and the corresponding leukemia by methylation arrays and whole-exome sequencing and found a variety of aberrations in both entities with deletions of CDKN2A/B as a recurrent finding.
We identified recurrent mutations involving the RAS-MAPK signaling pathway (MAP2K1, KRAS, NRAS, BRAF, PTPN11, NF1, CBL) in a majority (57%) of histiocytic sarcoma cases and report a clinical response to a MEK inhibitor (Cobimetinib) in a patient with a NF1-mutated histiocytic sarcoma.
Since CDKN2A deletion predisposes to development of HS in experimental models, the cytogenetic features of the patient's pre-B ALL may have predisposed to this change in lineage.
These genetic and translational observations establish a cooperative role of Pten and Ink4a/Arf in the development of HS and provide mechanistic insights into the pathogenesis of human HS.
These kinase alterations include activating mutations in A-Raf proto-oncogene, mitogen-activated protein kinase kinase 1, neuroblastoma rat sarcoma viral oncogene homolog, Kirsten rat sarcoma viral oncogene homolog, and phosphatidylinositol-4,5-bisphosphate 3 kinase, catalytic subunit α kinases in LCH and non-LCH; BRAF, anaplastic lymphoma receptor tyrosine kinase, and neurotrophic tyrosine kinase, receptor type 1 fusions, as well as the Ets variant 3-nuclear receptor coactivator 2 fusion in non-LCH; and mutations in the mitogen-activated protein kinase kinase kinase 1 and Harvey rat sarcoma viral oncogene homolog kinases in LCH and histiocytic sarcoma, respectively.
The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma.
The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma.
We investigated an atypical BRAF mutation, F595L, which was identified along with mutant HRAS in histiocytic sarcoma and also occurs in epithelial cancers, melanoma and neuroblastoma, and determined its interaction with mutant RAS.