A Novel EP300::PATZ1 Fusion Identified in A Patient With High-Grade Neuroepithelial Tumor
Cancer Genetics and Therapeutics
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Primary Categories:
- Cancer
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Secondary Categories:
- Cancer
Introduction
Neuroepithelial tumors, formerly known as primitive neuroectodermal tumors (PNET) of the central nervous system, are reclassified under embryonal tumors in the 2016 WHO Classification of Tumors of the Central Nervous System with two known involved genes: MN1 and BCOR. PATZ1 fusion (with MN1 and EWSR1)–positive neuroepithelial tumors are uncommon but are increasingly recognized as a unique molecular subtype of neoplasms that predominantly arise in children and young adults. Here, we report a novel EP300::PATZ1 fusion in a high-grade neuroepithelial tumor (HGNET) in a young boy.
Case Presentation
The patient, a previously healthy 5-year-old male, was admitted due to sudden onset of severe persistent headache, neck pain, and vomiting, unresponsive to medication.
Diagnostic Workup
The initial neurological examination was normal. A CT scan showed a right frontal lobe mass with a midline shift, and MRI confirmed the tumor's location in the posterior right frontal lobe. It had progressed to the thoracic spine (T6-T7) and the brainstem.
After craniotomy, histopathological examination revealed a cellular solid neoplasm predominantly composed of small, round and occasional spindled cells. Selected areas contained pleomorphic cells featuring enlarged, atypical nuclei and increased eosinophilic cytoplasm. Focal cartilaginous differentiation was noted.
Immunohistochemical (IHC) analysis showed positive staining for GFAP and OLIG2 in specific tumor areas, along with markedly increased reticulin deposition throughout the neoplasm. Desmin positivity was present in a subset of neoplastic cells. BRG1 and INI1 exhibited retained nuclear expression, while neurofilament protein supported a predominantly solid growth pattern. IHC was negative for H3 K27M, IDH1 R132H, and BRAF V600E. The Ki-67 labeling index was estimated at 40-60% in the hotspot areas. The histological features and immunoprofile were consistent with a high-grade neoplasm exhibiting sarcomatous characteristics. Differential diagnoses included sarcomas and high-grade neuroepithelial tumors with sarcomatous differentiation.
Several genetic studies were performed. Sanger sequencing was negative for internal tandem duplication (ITD) variant in exon 15 of the BCOR gene. FISH analysis ruled out EWSR1 rearrangement. Chromosome analysis revealed a complex karyotype including loss of chromosome 22, structural rearrangements of chromosome Y and 19, and gain of chromosome 21 and marker chromosomes. Microarray analysis revealed chromothripsis of chromosomes Y and 22 (which correlated with chromosome analysis) and monoallelic deletion of CDKN2A/B. The chromosome 22 chromothripsis interrupted several genes including PATZ1 and EP300. Methylation array profiling supported a neuroepithelial tumor with PATZ1-fusion. Finally, RNA sequencing confirmed that the chromosome 22 chromothripsis resulted in an in-frame fusion of EP300 exon 14 with PATZ1 exon 1 and increased expression of PATZ1. The combined histology, methylation and cyto/molecular genetic studies confirmed the diagnosis of a HGNET with PATZ1 fusion in this patient.
Treatment and Management
The patient underwent a frontal craniotomy for tumor resection, followed by multiple cycles of chemotherapy.
Outcome and Follow-Up
The patient experienced complications from tumor progression, including febrile neutropenia, C. difficile enteritis, and recurring neurological symptoms. Despite aggressive treatment, he passed away less than a year after diagnosis.
Discussion
Although PATZ1 fusions with other 5' partner genes, such as EWSR1 and MN1, have been reported, the EP300::PATZ1 fusion has not been previously documented in HGNET. Notably, 6 of 7 patients in a series of PATZ1 fusion-associated CNS tumors showed chromosome 22 chromothripsis. The current case also demonstrates chromosome 22 chromothripsis, supporting the hypothesis that PATZ1-CNS tumors may be defined by this chromosomal event as the mechanism of the PATZ1 fusion.
The MRI and histology in this case align with typical features of PATZ1 fusion tumors, including their proximity to the lateral ventricles, frequent posterior supratentorial location, and predominant spindle cell morphology.
Conclusion
We identified a new 5’partner, EP300, for PATZ1 fusion in HGNET, providing more information for defining the potential new sub-entity of CNS-HGNET with PATZ1 fusion.
Neuroepithelial tumors, formerly known as primitive neuroectodermal tumors (PNET) of the central nervous system, are reclassified under embryonal tumors in the 2016 WHO Classification of Tumors of the Central Nervous System with two known involved genes: MN1 and BCOR. PATZ1 fusion (with MN1 and EWSR1)–positive neuroepithelial tumors are uncommon but are increasingly recognized as a unique molecular subtype of neoplasms that predominantly arise in children and young adults. Here, we report a novel EP300::PATZ1 fusion in a high-grade neuroepithelial tumor (HGNET) in a young boy.
Case Presentation
The patient, a previously healthy 5-year-old male, was admitted due to sudden onset of severe persistent headache, neck pain, and vomiting, unresponsive to medication.
Diagnostic Workup
The initial neurological examination was normal. A CT scan showed a right frontal lobe mass with a midline shift, and MRI confirmed the tumor's location in the posterior right frontal lobe. It had progressed to the thoracic spine (T6-T7) and the brainstem.
After craniotomy, histopathological examination revealed a cellular solid neoplasm predominantly composed of small, round and occasional spindled cells. Selected areas contained pleomorphic cells featuring enlarged, atypical nuclei and increased eosinophilic cytoplasm. Focal cartilaginous differentiation was noted.
Immunohistochemical (IHC) analysis showed positive staining for GFAP and OLIG2 in specific tumor areas, along with markedly increased reticulin deposition throughout the neoplasm. Desmin positivity was present in a subset of neoplastic cells. BRG1 and INI1 exhibited retained nuclear expression, while neurofilament protein supported a predominantly solid growth pattern. IHC was negative for H3 K27M, IDH1 R132H, and BRAF V600E. The Ki-67 labeling index was estimated at 40-60% in the hotspot areas. The histological features and immunoprofile were consistent with a high-grade neoplasm exhibiting sarcomatous characteristics. Differential diagnoses included sarcomas and high-grade neuroepithelial tumors with sarcomatous differentiation.
Several genetic studies were performed. Sanger sequencing was negative for internal tandem duplication (ITD) variant in exon 15 of the BCOR gene. FISH analysis ruled out EWSR1 rearrangement. Chromosome analysis revealed a complex karyotype including loss of chromosome 22, structural rearrangements of chromosome Y and 19, and gain of chromosome 21 and marker chromosomes. Microarray analysis revealed chromothripsis of chromosomes Y and 22 (which correlated with chromosome analysis) and monoallelic deletion of CDKN2A/B. The chromosome 22 chromothripsis interrupted several genes including PATZ1 and EP300. Methylation array profiling supported a neuroepithelial tumor with PATZ1-fusion. Finally, RNA sequencing confirmed that the chromosome 22 chromothripsis resulted in an in-frame fusion of EP300 exon 14 with PATZ1 exon 1 and increased expression of PATZ1. The combined histology, methylation and cyto/molecular genetic studies confirmed the diagnosis of a HGNET with PATZ1 fusion in this patient.
Treatment and Management
The patient underwent a frontal craniotomy for tumor resection, followed by multiple cycles of chemotherapy.
Outcome and Follow-Up
The patient experienced complications from tumor progression, including febrile neutropenia, C. difficile enteritis, and recurring neurological symptoms. Despite aggressive treatment, he passed away less than a year after diagnosis.
Discussion
Although PATZ1 fusions with other 5' partner genes, such as EWSR1 and MN1, have been reported, the EP300::PATZ1 fusion has not been previously documented in HGNET. Notably, 6 of 7 patients in a series of PATZ1 fusion-associated CNS tumors showed chromosome 22 chromothripsis. The current case also demonstrates chromosome 22 chromothripsis, supporting the hypothesis that PATZ1-CNS tumors may be defined by this chromosomal event as the mechanism of the PATZ1 fusion.
The MRI and histology in this case align with typical features of PATZ1 fusion tumors, including their proximity to the lateral ventricles, frequent posterior supratentorial location, and predominant spindle cell morphology.
Conclusion
We identified a new 5’partner, EP300, for PATZ1 fusion in HGNET, providing more information for defining the potential new sub-entity of CNS-HGNET with PATZ1 fusion.