A 14-year-old boy presents with a 3-month history of progressive pain and swelling of the left femur. Plain radiograph shows a diaphyseal lytic lesion with an "onion-skin" periosteal reaction. Biopsy reveals small round blue cells with CD99+ membranous immunostaining. FISH analysis confirms the translocation marked **A** in the diagram. Which of the following best describes the molecular pathogenesis of this tumor?

Question

Accepted Answer

C. The EWSR1-FLI1 fusion protein acts as an aberrant transcription factor that reprograms mesenchymal progenitor cells and activates oncogenic transcription programs including NKX2-2 and GLI1. ## Why option 1 is correct

The translocation **A** — t(11;22)(q24;q12) EWSR1-FLI1 — is the hallmark of Ewing sarcoma family of tumors (ESFT), present in ~85% of cases. The chimeric EWSR1-FLI1 fusion protein functions as an aberrant transcription factor that reprograms hematopoietic and mesenchymal progenitor cells, activating aberrant transcription programs (NKX2-2, NR0B1, GLI1) and disrupting BAF chromatin remodeling complexes. This single fusion oncogene is sufficient to drive tumorigenesis. The clinical presentation (diaphyseal lytic lesion, onion-skin periosteal reaction, small round blue cells, CD99+) combined with FISH confirmation of EWSR1 break-apart establishes the diagnosis and confirms the molecular mechanism described in this option (WHO Bone & Soft Tissue 2020; COG AEWS1031).

## Why each distractor is wrong

- **Option 2**: SYT-SSX (t(X;18)) is the defining translocation of synovial sarcoma, not Ewing sarcoma. This fusion disrupts myogenic differentiation through a different mechanism and is not relevant to the EWSR1-FLI1 pathogenesis shown in structure **A**.
- **Option 3**: PAX3-FOXO1 (t(2;13)) is the characteristic translocation of alveolar rhabdomyosarcoma, not Ewing sarcoma. Although it does activate PI3K/AKT signaling, this is not the pathogenic mechanism of the **A** translocation.
- **Option 4**: FUS-DDIT3 (t(12;16)) defines myxoid liposarcoma and impairs lipoprotein lipase function. This is entirely unrelated to the EWSR1-FLI1 fusion and the transcriptional reprogramming that characterizes Ewing sarcoma.

**High-Yield:** EWSR1-FLI1 (t(11;22)) = Ewing sarcoma; acts as aberrant transcription factor activating NKX2-2, GLI1; CD99+ small round blue cells; onion-skin periosteal reaction; VDC/IE chemotherapy backbone.

[cite: WHO Bone & Soft Tissue 2020; COG AEWS1031]

Answer

A. The PAX3-FOXO1 fusion protein constitutively activates the PI3K/AKT pathway, leading to uncontrolled myoblast proliferation

Answer

B. The FUS-DDIT3 fusion protein impairs normal lipoprotein lipase function and causes lipid accumulation in tumor cells

Answer

D. The SYT-SSX fusion protein disrupts myogenic differentiation by inhibiting PAX3-dependent transcription

Explanation

Why option 1 is correct

Why each distractor is wrong

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