A novel BRD4‐LEUTX fusion in a pediatric sarcoma with epithelioid morphology and diffuse S100 expression

Abstract

Malignant epithelioid soft tissue tumors encompass a wide spectrum of lesions. Among them, Epithelioid Malignant Peripheral Nerve Sheath Tumors (MPNST) constitute a distinct subgroup, accounting for <5% of all MPNST. Epithelioid MPNST are infrequently associated with neurofibromatosis type 1, occasionally arise in a schwannoma and show diffuse S100 and CD34 expression, often combined with INI‐1 loss. However, the molecular mechanisms underlying the tumorigenesis of epithelioid MPNST remain largely unknown. We describe a case of a 10‐year‐old girl with an epithelioid malignancy of the orbit. The tumor proved positive for S100, CD34 and SOX10, and, although INI‐1 expression was maintained, the overall features suggested the possibility of an epithelioid MPNST, arising in an unusual location. NGS analysis revealed a novel in‐frame BRD4‐LEUTX fusion gene. LEUTX plays an important role in embryonal genome activation and its expression is mostly suppressed postnatally. We were able to detect increased levels of LEUTX transcript in the tumor, indicating that BRD4‐LEUTX fusion leads to LEUTX re‐activation. To our knowledge, this fusion has never been reported previously. Whether the current case represents an example of epithelioid MPNST or a distinct tumor entity remains to be determined.

Clinicopathological and molecular characterization of a case classified by DNA‑methylation profiling as “CNS embryonal tumor with BRD4–LEUTX fusion”

“…BRD4–LEUTX fusion is a rare fusion which has only been described in the literature in one infant CNS embryonal tumor ( BRD4 exon 11- LEUTX exon 2 fusion) in a comprehensive molecular profiling study of 252 high-risk pediatric cancers [ 19 ]. Outside the CNS, this fusion has been reported in one pediatric epithelioid malignant peripheral nerve sheath tumor and an alveolar rhabdomyosarcoma [ 2 , 4 ]. Even though they share the same molecular alteration, the tumor locations, morphologies and IHC profiles were drastically different between our case and the BRD4–LEUTX pediatric sarcoma described by Barresi et al [ 2 ].…”

“…Outside the CNS, this fusion has been reported in one pediatric epithelioid malignant peripheral nerve sheath tumor and an alveolar rhabdomyosarcoma [ 2 , 4 ]. Even though they share the same molecular alteration, the tumor locations, morphologies and IHC profiles were drastically different between our case and the BRD4–LEUTX pediatric sarcoma described by Barresi et al [ 2 ]. Other LEUTX gene fusions including CIC gene ( CIC–LEUTX fusion) were already reported in very few cases including one CNS embryonal tumor and an anaplastic pleomorphic astrocytoma [ 8 , 16 ].…”

A case of CIC‐rearranged sarcoma with CIC‐LEUTX gene fusion in spinal cord

“… 5 Barresi et al . 20 recently reported a case of malignant epithelioid peripheral nerve sheath tumor in a child with BRD4‐LEUTX fusion. Increased levels of LEUTX transcripts in the tumor could be detected in this case, suggesting that the BRD4‐LEUTX fusion leads to LEUTX reactivation.…”

NovelHNRNPM::LEUTXfusion resulting from chromothripsis of chromosome 19 in a pediatric undifferentiated small round cell neoplasm

“…Although the relative importance of individual 5 0 fusion partners to functional activation of LEUTX fusions is insufficiently understood, findings from this analysis suggest that tumors harboring CIC::LEUTX are molecularly distinct from the HNRNPM::LEUTX-fused tumor described here. Other tumor-associated LEUTX fusions include BRD4::LEUTX in a soft tissue epithelioid malignant tumor, 6 and KAT6A::LEUTX fusion in a therapy-related case of acute myeloid leukemia. 7 The HNRNPM (heterogeneous nuclear ribonucleoprotein M) gene, located on 19p13.2, encodes a pre-mRNA binding protein that regulates a multigenic splicing program to maintain cell proliferation and influences pre-mRNA processing and other aspects of mRNA metabolism and transport.…”

“…Previous reports of LEUTX fusions in other tumors involving similar rearrangement breakpoints supported the interpretation of the current fusion as a driver alteration in this tumor. [3][4][5][6][7][8] No structural alterations or overexpression of BCOR was identified by RNA sequencing. A few sequencing reads supported the presence of the previously reported MLLT1::ACTN4 and SMARCA4::SCAF1 fusions, but the data did not reach reportable criteria.…”