BEND2

Overview

BEND2 (BEN Domain Containing 2) encodes a protein characterized by its C-terminal BEN domain, a conserved nucleic-acid-binding module implicated in chromatin organization and transcriptional regulation. BEND2 is the 3’ fusion partner in EWSR1::BEND2 gene fusions, which define a rare subset of undifferentiated small round cell sarcomas (EWSR1-non-ETS group) and a subset of astroblastomas. The EWSR1::BEND2 fusion places the N-terminal transcriptional activation domain of EWSR1 upstream of the BEND2 BEN domain, generating a putative aberrant transcription factor.

Alterations observed in the corpus

  • 3’ fusion partner in an EWSR1::BEND2 in-frame fusion (EWSR1 exon 10 :: BEND2 exon 2) detected by break-apart FISH and RNA-seq in a primary sarcoma of the urinary bladder; the EWSR1 breakpoint (exon 10) differs from those reported in CNS astroblastoma cases involving MN1::BEND2 or EWSR1::BEND2 PMID:28199314

Cancer types (linked)

  • EWSR1::BEND2 sarcoma of the urinary bladder (first reported case at this anatomical site); the fusion has also been described in astroblastoma (ASTB), salivary gland, trachea, pancreas, sinonasal cavity, and bone PMID:28199314

Co-occurrence and mutual exclusivity

  • Co-occurs with PTEN loss (10q deletion) in the reported bladder sarcoma case; SMARCB1 and SMARCA4 protein expression retained (IHC), ruling out SWI/SNF-deficient diagnoses PMID:28199314
  • MN1::BEND2 fusions characterize a distinct epigenetic subtype of astroblastoma; MN1 is the canonical CNS fusion partner, with EWSR1 representing an alternative in both CNS and non-CNS sites PMID:28199314

Therapeutic relevance

  • No direct therapeutic agent targets the EWSR1::BEND2 fusion; Ewing-sarcoma-like chemotherapy (ISG/SSG IV protocol) was used in the reported bladder sarcoma patient, controlling primary disease but failing to control pelvic and pulmonary metastases PMID:28199314
  • Co-occurring PTEN loss was identified as a potential biomarker for mTOR or PARP inhibition but was not pursued therapeutically in this case PMID:28199314

Open questions

  • Whether EWSR1::BEND2 sarcomas at different anatomical sites form a single molecular subgroup or multiple distinct entities remains unresolved; the exon 10 breakpoint in bladder cases differs from CNS astroblastoma breakpoints PMID:28199314
  • Methylation classifier prediction for the reported case was low (score 0.364 for astroblastoma), and no sarcoma classifier match was obtained — epigenetic identity is unresolved PMID:28199314
  • How WHO classification should evolve to accommodate proliferating EWSR1-non-ETS fusion partners (BEND2, NFATC2, PATZ1, POU2AF3) is an open question PMID:28199314

Sources

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