Genomic profiling of primary histiocytic sarcoma reveals two molecular subgroups

Abstract

Histiocytic sarcoma is a rare malignant neoplasm that may occur <i>de novo</i> or in the context of a previous hematologic malignancy or mediastinal germ cell tumor. Here, we performed whole exome sequencing and RNA-sequencing (RNA-Seq) on 21 archival cases of primary histiocytic sarcoma. We identified a high number of genetic alterations within the RAS/RAF/MAPK pathway in 21 of 21 cases, with alterations in <i>NF1</i> (6 of 21), <i>MAP2K1</i> (5 of 21), <i>PTPN11</i> (4 of 21), <i>BRAF</i> (4 of 21), <i>KRAS</i> (4 of 21), <i>NRAS</i> (1 of 21), and <i>LZTR1</i> (1 of 21), including single cases with homozygous deletion of <i>NF1</i>, high-level amplification of <i>PTPN11</i>, and a novel <i>TTYH3-BRAF</i> fusion. Concurrent <i>NF1</i> and <i>PTPN11</i> mutations were present in 3 of 21 cases, and 5 of 7 cases with alterations in <i>NF1</i> and/or <i>PTPN11</i> had disease involving the gastrointestinal tract. Following unsupervised clustering of gene expression data, cases with <i>NF1</i> and/or <i>PTPN11</i> abnormalities formed a distinct tumor subgroup. A subset of <i>NF1/PTPN11</i> wild-type cases had frequent mutations in B-cell lymphoma associated genes and/or clonal IG gene rearrangements. Our findings expand the current understanding of the molecular pathogenesis of this rare tumor and suggest the existence of a distinct subtype of primary histiocytic sarcoma characterized by <i>NF1/PTPN11</i> alterations with predilection for the gastrointestinal tract.