FUS-NFATC2 or EWSR1-NFATC2 Fusions Are Present in a Large Proportion of Simple Bone Cysts

Abstract

A simple bone cyst (SBC) is a benign bone lesion of unknown etiology. It can be differentiated from an aneurysmal bone cyst (ABC) by radiologic and histopathologic features, as well as by the absence of fusions of the USP6 gene characteristic of an ABC. In an attempt to differentiate between ABC and SBC in a recurrent bone cyst, we performed targeted RNA sequencing and found an EWSR1-NFATC2 fusion and no fusion of the USP6 gene. We subsequently analyzed additional 10 cysts, consistent with SBCs after radiologic-pathologic correlation, for the presence of an NFATC2 gene fusion, by targeted RNA sequencing, reverse-transcription polymerase chain reaction (RT-PCR) and Sanger sequencing, and fluorescent in situ hybridization. Targeted RNA sequencing showed a FUS-NFATC2 fusion in 4 of 11 SBCs and an EWSR1-NFATC2 fusion in 2 of 11 SBCs. No fusion was identified in 3 SBCs and the analysis was not successful in 2 SBCs because of the low quantity or poor quality of isolated RNA. All the 6 fusions detected by targeted RNA sequencing were confirmed by RT-PCR and Sanger sequencing, and 5 of the 6 fusions by fluorescent in situ hybridization. An additional FUS-NFATC2 fusion was identified by RT-PCR, Sanger sequencing, and fluorescent in situ hybridization in 1 of the 3 cases negative for fusions by targeted RNA sequencing. At least a large subset of SBCs represents cystic neoplasms characterized by FUS-NFATC2 or EWSR1-NFATC2 fusions, which also define a group of distinct, rare “Ewing-like” sarcomas that predominantly arise in long bones. Our results provide additional evidence of the existence of benign lesions with FUS-NFATC2 or EWSR1-NFATC2 fusions. Although they can recur locally in a nondestructive manner, their clinical course and possible relation to sarcoma with EWSR1-NFATC2 or FUS-NFATC2 fusion remains to be elucidated.

Identification of EWSR1–NFATC2 fusion in simple bone cysts

“…Although absent in the above-mentioned mimics, the fibrin-like deposits are also absent in a subset of simple bone cysts, including seven of 15 (47%) specimens from 11 patients in the study by Pizem et al 19 and two of 10 (20%) specimens from nine patients in the current study. When the radiological and histological features are equivocal, the identification of EWSR1-NFATC2 or FUS-NFATC2 fusion in a subset of simple bone cysts may allow one to make this diagnosis.…”

“…NFATC2 rearrangements, which are characteristic of a subset of aggressive round cell sarcomas, [12][13][14][15][16][17][18] have been recently described in benign-appearing bone cysts. 14,19 Bode-Lesniewska et al reported a bone cyst in the humerus of a 12-year-old boy, showing aneurysmal bone cyst-like histology and harbouring an FUS-NFATC2 fusion. 14 Pizem et al identified EWSR1-NFATC2 or FUS-NFATC2 fusions in six of 11 simple bone cysts.…”

“…NFATC2 rearrangements, which are characteristic of a subset of aggressive round cell sarcomas, 12–18 have been recently described in benign‐appearing bone cysts 14,19 . Bode‐Lesniewska et al .…”

Genetic characteristics and molecular diagnostics of bone tumors

“…FUS-DDIT3 EWSR1-DDIT3 Alveolar Soft Part Sarcoma [139,140] t(X;17)(p11;q25) ASPCR1-TFE3 Undifferentiated Round Cell Sarcomas [4,18,91,[141][142][143][144] t(4;19)(q35;q13) t(10;19)(q26;q13) Paracentric inv(X)(p11.4p11.22) t(20;22)(q13.2;q12.2)…”

Differenzialdiagnose expansiver Osteolysen im Kiefer

“…Kürettagen sind therapeutisch i. d. R. ausreichend, auch Spontanheilungen kommen vor [22]. Interessanterweise sind bei solitären Knochenzysten im peripheren Skelett vor Kurzem FUS-NFATC2 und EWSR1-NFATC2-Fusionstranskripte nachgewiesen worden, die zuvor nur bei hochmalignen und undifferenzierten Rundzellsarkomen bekannt waren [23]. Es bleibt abzuwarten, ob solche Veränderungen auch bei solitären Knochenzysten im Kiefer vorkommen, in jedem Fall handelt es sich um benigne Läsionen ohne Entartungspotenzial.…”