Novel fusion genes in spindle cell rhabdomyosarcoma: The spectrum broadens

Abstract

Rhabdomyosarcoma (RMS) encompasses a heterogeneous group of tumors with striated muscle differentiation. RMSs are classified as alveolar, embryonal, spindle cell/sclerosing, and pleomorphic types and molecular analysis of these tumors has identified aberrations that are useful in their further subclassification. Spindle cell rhabdomyosarcoma (SpRMS) is uncommon and has been described with VGLL2 fusions, EWSR1/FUS-TFCP2 rearrangements, and myoD1 mutations-the mutations are associated with significantly different prognoses. In addition, the NCOA2-MEIS1 fusion gene was recently described in two primary intraosseous RMS that contained spindle cell components. Herein, we report three cases of SpRMS harboring different novel fusion genes, one possessing EP300-VGLL3, a second with NCOA2-MEIS1 and CAV1-MET, and the third case had HMGA2-NEGR1 and multiple amplified genes.

Recurrent VGLL3 fusions define a distinctive subset of spindle cell rhabdomyosarcoma with an indolent clinical course and striking predilection for the head and neck

“…Taken together, five of our cases and the one reported recently by Montoya‐Cerrillo et al 15 shared intramuscular location in head and neck, bland histomorphology, minimal to variable rhabdomyogenic differentiation, VGLL3 rearrangement, and indolent clinical behavior. Moreover, four of the seven cases were located in the tongue.…”

“…Notably, the VGLL3 fusion products identified in four of these tumors are novel and have not been reported previously in any entity. A single tumor with similar histology, but more prominent myogenin and MyoD1 expression was included in a recent series of spindle cell RMS published by Montoya‐Cerrillo et al 15 This tumor (which is similar to our Cases 2–6) presented as a submucosal muscle‐centered mass in the ventral left mid‐tongue of a 36‐year‐old male, who remained disease‐free 1 year after surgical treatment. RNA sequencing revealed an EP300::VGLL3 fusion similar to the fusion product detected in two of our cases.…”

“…14 To our knowledge only a single case of myogenic sarcoma has been recently reported to harbor a VGLL3 fusion (reported as spindle cell RMS). 15 We herein characterize a distinct spindle cell RMS occurring in adults with predilection for the head and neck, defined by recurrent novel VGLL3 fusions and characterized by bland morphology, limited rhabdomyogenic differentiation, and indolent clinical behavior.…”

Molecular testing of rhabdomyosarcoma in clinical trials to improve risk stratification and outcome: A consensus view from European paediatric Soft tissue sarcoma Study Group, Children's Oncology Group and Cooperative Weichteilsarkom-Studiengruppe

“…The limited number of cases with EWSR1/FUS-TFCP2 rearrangements tends to show a hybrid spindled and epithelioid morphology with a frequent expression of cytokeratins and ALK and have poor outcomes [39], while those with NCOA2-MEIS1 fusions show a primitive, fascicular pattern. Additionally, new fusion genes have recently described in spindle cell RMS, including EP300-VGLL3, CAV1-MET and HMGA2-NEGR1 [40]. More data on all of these rare subtypes, summarised in Fig.…”

Shedding a Light on the Challenges of Adolescents and Young Adults with Rhabdomyosarcoma

“…The function of the TFCP2 fusion has not been completely clarified (e.g., aberrant transcription activity, interaction with RNA binding). RMS with TFCP2 fusions do present mostly as intra-osseous disease, especially located in facial bones in young adults, but extra-osseous occurrence has been recently reported [ 63 , 64 ]. The limited data do not allow definite conclusions, however, the clinical behavior appears to be extremely aggressive [ 56 , 60 ].…”