A 28-year-old man presents with a 6-month history of a slowly enlarging, painful mass in the left knee region. MRI shows a 7 cm deep periarticular heterogeneous mass with hemorrhagic and cystic areas. Biopsy reveals a biphasic pattern with spindle cells and epithelial glandular components. FISH analysis confirms the translocation marked **A** in the diagram. Which of the following best describes the molecular pathogenesis of this tumor?
A. Ejection of BAF47 (SMARCB1) from the SWI/SNF chromatin remodeling complex, leading to aberrant transcriptional reprogramming and silencing of polycomb targets
B. Constitutive activation of tyrosine kinase signaling through EWS-FLI1 fusion protein, resulting in uncontrolled cell proliferation
C. Impaired DNA repair through FUS-DDIT3 fusion, causing accumulation of chromosomal instability and genomic mutations
D. Activation of PAX3-FOXO1 fusion protein, which drives rhabdomyosarcoma differentiation through myogenic transcription factors
Explanation
Why option 1 is right
The translocation marked A, t(X;18)(p11.2;q11.2), creates the SS18-SSX fusion oncoprotein that is pathognomonic for synovial sarcoma. The molecular mechanism involves fusion of SS18 (a transcriptional coactivator normally part of BAF/SWI/SNF chromatin remodeling complexes) with SSX (a transcriptional repressor on Xp11). This aberrant fusion complex ejects BAF47 (SMARCB1/INI1) from the SWI/SNF complex, fundamentally reprogramming chromatin architecture and silencing polycomb target genes—the defining pathogenic mechanism (WHO Bone & Soft Tissue 2020; NCCN STS 2024).
Why each distractor is wrong
Option 2: This describes the EWS-FLI1 fusion (t(11;22), marked B), which is pathognomonic for Ewing sarcoma, not synovial sarcoma. The mechanism involves tyrosine kinase activation, not chromatin remodeling.
Option 3: This describes the PAX3-FOXO1 fusion (t(2;13), marked C), which defines alveolar rhabdomyosarcoma and activates myogenic transcription factors—a completely different sarcoma entity and pathogenic pathway.
Option 4: This describes the FUS-DDIT3 fusion (t(12;16), marked D), which is characteristic of myxoid liposarcoma and causes impaired DNA repair and genomic instability, not chromatin remodeling dysfunction.
High-YieldNEET PG
SS18-SSX fusion → BAF47 ejection from SWI/SNF → chromatin reprogramming = synovial sarcoma pathogenesis; this is the ONLY soft tissue sarcoma defined by chromatin complex disruption rather than kinase activation.
WHO Bone & Soft Tissue 2020; NCCN STS 2024
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