Identification of diverse activating mutations of the RAS-MAPK pathway in histiocytic sarcoma

• Published in: Modern pathology Vol. 32; no. 6; pp. 830 - 843
• Main Authors: Shanmugam, Vignesh, Griffin, Gabriel K., Jacobsen, Eric D., Fletcher, Christopher D. M., Sholl, Lynette M., Hornick, Jason L.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2019; Elsevier Limited
• Subjects: 1-Phosphatidylinositol 3-kinase; 692/420/755; 692/699/67/69; 82/51; Adolescent; Adult; Aged; Aged, 80 and over; B-cell lymphoma; Child; Cyclin-dependent kinase 4; Cyclin-dependent kinase inhibitors; Female; Histiocytic Sarcoma - genetics; Histiocytic Sarcoma - pathology; Histiocytosis; Humans; INK4 protein; Laboratory Medicine; Langerhans cell histiocytosis; Lymphocytes B; Macrophages; Male; MAP kinase; MAP Kinase Signaling System - genetics; Medicine; Medicine & Public Health; MEK inhibitors; Middle Aged; Mutation; Next-generation sequencing; Pathology; PTEN protein; ras Proteins - genetics; Sarcoma; Signal transduction; TOR protein; Tumors; Young Adult
• ISSN: 0893-3952; 1530-0285; 1530-0285
• DOI: 10.1038/s41379-018-0200-x

Recent studies have demonstrated recurrent activating mutations involving the classical MAPK and PI3K signaling pathways in a large proportion of histiocytic neoplasms, such as Langerhans cell histiocytosis. However, very little is known about the molecular genetics of histiocytic sarcoma, a rare aggressive malignant neoplasm that shows pathologic characteristics of mature macrophages. Here we report the genomic characteristics of a large cohort of histiocytic sarcomas ( n  = 28) using a targeted next-generation sequencing approach to identify driver alterations. 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. A smaller subset of cases (21%) also showed mutations resulting in activation of the PI3K signaling pathway ( PTEN , MTOR , PIK3R1 , PIK3CA ). In addition, the tumor-suppressor gene CDKN2A was the most frequently altered gene (46%). Further, a subset of histiocytic sarcoma cases shows striking molecular genetic similarities to B cell lymphomas, supporting a clonal relationship between B cell neoplasms and a subset of histiocytic sarcomas. These findings support a cooperative role for MAPK, PI3K, and cyclin-CDK4/6-INK4 signaling in the pathogenesis of histiocytic sarcoma and provide a rational basis for targeting these pathways.