Neuregulin 1 (NRG1) fusion‐positive high‐grade spindle cell sarcoma: A distinct group of soft tissue tumors with metastatic potential

Abstract

Neuregulin 1 (NRG1) is an epidermal growth factor (EGF)-like ligand that activates receptor tyrosine kinases of the ErbB family of receptors. NRG1 gene fusions, which are rare (<1%) but recurrent events in solid tumors, are an emerging oncogenic driver that is potentially actionable using ErbB-targeted tyrosine kinase inhibitors. Largely characterized only in carcinomas, we describe three cases of NRG1-rearranged sarcomas. The patients were all female, aged 32-47 years old. Two cases were deep-seated tumors in the lower extremities (right thigh and calf); one case presented as a uterine mass. The tumors measured 9-11.5 cm in the greatest dimensions. Histologically, all three tumors were highgrade spindle cell sarcomas composed of monomorphic spindle cells arranged in interlacing fascicles. The tumor cells were set in the loose collagenous stroma with branching, curvilinear thin-walled vasculature in the background. Cytologically, the neoplastic cells displayed ovoid to fusiform nuclei with finely stippled chromatin, inconspicuous nucleoli, scant to moderate clear to eosinophilic cytoplasm, occasional cytoplasmic vacuoles, and elongated cytoplasmic processes. Mitotic activity was elevated (> 20/10 high power fields) and tumor necrosis was present. None of the tumors expressed lineage-specific immunophenotypical markers. Targeted RNA-sequencing uncovered gene fusions involving NRG1 and the 5 0 untranslated regions of PPHLN1, HMBOX1, or MTUS1. In all cases, the Cterminal EGF-like domain of NRG1 was preserved in the predicted chimeric protein product. All three patients developed metastatic disease within 2 years from initial presentation and were alive with disease at last follow-up (mean follow-up period = 19 months). In conclusion, we present the first case series of NRG1-rearranged sarcomas characterized by high-grade fascicular spindle cell morphology, non-specific immunoprofile, and aggressive clinical behavior. Further studies are needed to determine whether this distinct subgroup of spindle cell sarcomas are amenable to targeted therapies.

Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer

“…NRG1 fusions are found in a variety of forms and cancers (Table 2 ) [ 23 , 29 , 54 – 61 , 70 – 73 ]. For example, NRG1 fusions with CD74 are predominantly seen in non-small cell lung cancers (NSCLCs) [ 54 , 55 , 58 , 59 , 73 ], the NOTCH2 - NRG1 fusion in gallbladders cancers [ 54 ], and the CDH1 - NRG1 fusion in pancreatic ductal adenocarcinoma [ 26 , 54 , 55 , 71 , 72 ] (Table 2 ).…”

HMBOX1, a member of the homeobox family: current research progress

“…As a partner gene, HMBOX1 has also been observed to fuse with several key genes in tumor development. Neuregulin 1-HMBOX1 fusion has been reported in high-grade spindle cell sarcomas [ 49 ], as well as an aplastic lymphoma kinase–HMBOX1 fusion in myxoid spindle cell neoplasm [ 50 ]. However, limited details regarding these cases were obtained, and future studies are needed to better characterize the role of HMBOX1 fusion in tumorigenesis and development.…”

Targeting the EGF receptor family in non-small cell lung cancer—increased complexity and future perspectives

“…Since then, multiple fusion partners (e.g., CD74-NRG1 , SLC3A2-NRG1 and VAMP2-NRG1) have been identified 144 . Although NRG1 fusions occur at low frequency (<1%) across carcinomas 145 and in mesenchymal tumors 146 , they are enriched in several cancer types, including oncogenic driver-negative NSCLC, and in mucinous lung adenocarcinomas 147 . Most of the resulting oncoproteins retain the EGF-like domain of NRG1 and thus have been predicted to be functional in activating the ERBB2-ERBB3 heterodimer and downstream signaling, thus supporting a therapeutic paradigm of ERBB2/ERBB3 inhibition 143 , 144 , 148 .…”