Optical Genome Mapping Identifies a Novel Pediatric Embryonal Tumor Subtype with a ZNF532-NUTM1 Fusion [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA938115 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23602670_1.fastq.gz | Fastqsanger.gz | |||
| SRR23602670_2.fastq.gz | Fastqsanger.gz |
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Project description:Molecular characteristics of pediatric brain tumors have not only allowed for tumor subgrouping but have introduced novel treatment options for patients with specific tumor alterations. Therefore, an accurate histologic and molecular diagnosis is critical for optimized management of all pediatric patients with brain tumors, including central nervous system embryonal tumors. We present a case where optical genome mapping identified a ZNF532-NUTM1 fusion in a patient with a unique tumor best characterized histologically as a central nervous system embryonal tumor with rhabdoid features. Additional analyses including immunohistochemistry for NUT protein, methylation array, whole genome, and RNA-sequencing was done to confirm the presence of the fusion in the tumor. This is the first description of a pediatric patient with a ZNF532-NUTM1 fusion, yet the histology of this tumor is similar to that of adult cancers with ZNF-NUTM1 fusions and other NUTM1-fusion positive brain tumors reported in literature. Although rare, the distinct pathology and underlying molecular characteristics of these tumors separate them from other embryonal tumors. Therefore, the NUTM-rearrangement appears to define a novel subgroup of pediatric central nervous system embryonal tumors with rhabdoid/epithelioid features that may have a unique response to treatment. Screening for a NUTM1-rearrangement should be considered for all patients with unclassified central nervous system tumors with rhabdoid features to ensure accurate diagnosis so this can ultimately inform therapeutic management for these patients.
2023-02-28 | GSE226220 | GEO
Project description:Molecular characteristics of pediatric brain tumors have not only allowed for tumor subgrouping but have introduced novel treatment options for patients with specific tumor alterations. Therefore, an accurate histologic and molecular diagnosis is critical for optimized management of all pediatric patients with brain tumors, including central nervous system embryonal tumors. We present a case where optical genome mapping identified a ZNF532-NUTM1 fusion in a patient with a unique tumor best characterized histologically as a central nervous system embryonal tumor with rhabdoid features. Additional analyses including immunohistochemistry for NUT protein, methylation array, whole genome, and RNA-sequencing was done to confirm the presence of the fusion in the tumor. This is the first description of a pediatric patient with a ZNF532-NUTM1 fusion, yet the histology of this tumor is similar to that of adult cancers with ZNF-NUTM1 fusions and other NUTM1-fusion positive brain tumors reported in literature. Although rare, the distinct pathology and underlying molecular characteristics of these tumors separate them from other embryonal tumors. Therefore, the NUTM-rearrangement appears to define a novel subgroup of pediatric central nervous system embryonal tumors with rhabdoid/epithelioid features that may have a unique response to treatment. Screening for a NUTM1-rearrangement should be considered for all patients with unclassified central nervous system tumors with rhabdoid features to ensure accurate diagnosis so this can ultimately inform therapeutic management for these patients.
2023-02-28 | GSE225965 | GEO
Project description:Optical Genome Mapping Identifies a Novel Pediatric Embryonal Tumor Subtype with a ZNF532-NUTM1 Fusion [methylation]
| PRJNA939180 | ENA
Project description:NUT carcinoma (NC) is an aggressive cancer with no effective treatment. About 70% of NUT carcinoma is associated with chromosome translocation events that lead to the formation of a BRD4::NUTM1 fusion gene. Because the BRD4::NUTM1 gene is unequivocally cytotoxic when ectopically expressed in cell lines, questions remain on whether the fusion gene can initiate NC. Here, we report the first genetically engineered mouse model (GEMM) for NUT carcinoma that recapitulates the t(15;19) chromosome translocation in mice. We demonstrated that the mouse t(2;17) syntenic chromosome translocation, forming the Brd4::Nutm1 fusion gene, could induce aggressive carcinomas in mice. The tumors present histopathological and molecular features similar to human NC, with an enrichment of undifferentiated cells. Similar to the reports of human NC incidence, Brd4::Nutm1 can induce NC from a broad range of tissues with a strong phenotypical variability. The consistent induction of poorly differentiated carcinoma demonstrated a strong reprogramming activity of BRD4::NUTM1. The new mouse model provided a critical preclinical model for NC that will lead to better understanding and therapy development for NC.
2024-05-07 | GSE263567 | GEO
Project description:NUT carcinoma (NC) is an aggressive cancer with no effective treatment. About 70% of NUT carcinoma is associated with chromosome translocation events that lead to the formation of a BRD4::NUTM1 fusion gene. Because the BRD4::NUTM1 gene is unequivocally cytotoxic when ectopically expressed in cell lines, questions remain on whether the fusion gene can initiate NC. Here, we report the first genetically engineered mouse model (GEMM) for NUT carcinoma that recapitulates the t(15;19) chromosome translocation in mice. We demonstrated that the mouse t(2;17) syntenic chromosome translocation, forming the Brd4::Nutm1 fusion gene, could induce aggressive carcinomas in mice. The tumors present histopathological and molecular features similar to human NC, with an enrichment of undifferentiated cells. Similar to the reports of human NC incidence, Brd4::Nutm1 can induce NC from a broad range of tissues with a strong phenotypical variability. The consistent induction of poorly differentiated carcinoma demonstrated a strong reprogramming activity of BRD4::NUTM1. The new mouse model provided a critical preclinical model for NC that will lead to better understanding and therapy development for NC.
2024-05-07 | GSE263558 | GEO
Project description:NUT carcinoma (NC) with mesenchymal differentiation have rarely been described in the literature. In this report, we describe the characterization of two cases of high grade spindle cell sarcoma harboring a novel MGA-NUTM1 fusion. Whole genome sequencing identified the presence of complex rearrangements resulting in a MGA-NUTM1 fusion gene in the absence of other significant somatic mutations. The fusion protein was predicted to retain nearly the entire protein sequence of both MGA (exons 1-22) and NUTM1 (exons 3-8). In contrast to typical cases of NC, these cases were successfully treated with aggressive local control measures (surgery and radiation) and both patients remain alive without disease. These cases describe a new subtype of NUTM1-rearranged tumors warranting expansion of diagnostic testing to evaluate for the presence of MGA-NUTM1 or alternative NUTM1 gene fusions in the diagnostic workup of high grade spindle cell sarcomas or small round blue cell tumors of ambiguous lineage.
| EGAS00001003341 | EGA
Project description:NUTM1-rearrangement (NUTM1-r) represents a significant subset of infant B-ALL, particularly prevalent in cases lacking KMT2A-rearrangements (KMT2A-r). However, the underlying molecular mechanisms for the characteristic leukemia have not been fully elucidated. Our comprehensive analysis reveals that NUTM1-r infant leukemia is characterized by a unique transcriptomic and epigenetic landscape with global hypomethylation, delineating a discrete leukemia entity. Functional interrogation of the BRD9-NUTM1 fusion demonstrates its dual role in promoting B-lineage commitment while conferring leukemic stem cell properties. Strikingly, single transduction of BRD9-NUTM1 is sufficient to induce serially-transplantable pro-B-like leukemia in vivo, recapitulating key features of human NUTM1-r B-ALL, including NUTM1 overexpression, skewed B cell transcriptional programs, and low CD34 expression. Mechanistically, BRD9-NUTM1 expression gives rise to distinctive open chromatin regions with global enhancement of H3K27Ac, particularly at loci associated with Myc, NF-κB, and posterior Hoxa genes. Notably, BRD9-NUTM1 leukemic cells responded robustly to cytarabine, in contrast to the relative resistance observed in KMT2A-r leukemias. Interestingly, our findings highlight a discrepancy observed in the clinical behavior of NUTM1-r leukemias, where the transformed cells display characteristics of stemness, yet tend to lose these properties under chemotherapy due to the dependence on active transcription. Our findings delineate the unique molecular profile of NUTM1-r leukemias, suggesting opportunities for targeted therapies that exploit these specific vulnerabilities.
2026-04-22 | GSE276676 | GEO
Project description:NUTM1-rearrangement (NUTM1-r) represents a significant subset of infant B-ALL, particularly prevalent in cases lacking KMT2A-rearrangements (KMT2A-r). However, the underlying molecular mechanisms for the characteristic leukemia have not been fully elucidated. Our comprehensive analysis reveals that NUTM1-r infant leukemia is characterized by a unique transcriptomic and epigenetic landscape with global hypomethylation, delineating a discrete leukemia entity. Functional interrogation of the BRD9-NUTM1 fusion demonstrates its dual role in promoting B-lineage commitment while conferring leukemic stem cell properties. Strikingly, single transduction of BRD9-NUTM1 is sufficient to induce serially-transplantable pro-B-like leukemia in vivo, recapitulating key features of human NUTM1-r B-ALL, including NUTM1 overexpression, skewed B cell transcriptional programs, and low CD34 expression. Mechanistically, BRD9-NUTM1 expression gives rise to distinctive open chromatin regions with global enhancement of H3K27Ac, particularly at loci associated with Myc, NF-κB, and posterior Hoxa genes. Notably, BRD9-NUTM1 leukemic cells responded robustly to cytarabine, in contrast to the relative resistance observed in KMT2A-r leukemias. Interestingly, our findings highlight a discrepancy observed in the clinical behavior of NUTM1-r leukemias, where the transformed cells display characteristics of stemness, yet tend to lose these properties under chemotherapy due to the dependence on active transcription. Our findings delineate the unique molecular profile of NUTM1-r leukemias, suggesting opportunities for targeted therapies that exploit these specific vulnerabilities.
2026-04-22 | GSE276675 | GEO
Project description:NUTM1-rearrangement (NUTM1-r) represents a significant subset of infant B-ALL, particularly prevalent in cases lacking KMT2A-rearrangements (KMT2A-r). However, the underlying molecular mechanisms for the characteristic leukemia have not been fully elucidated. Our comprehensive analysis reveals that NUTM1-r infant leukemia is characterized by a unique transcriptomic and epigenetic landscape with global hypomethylation, delineating a discrete leukemia entity. Functional interrogation of the BRD9-NUTM1 fusion demonstrates its dual role in promoting B-lineage commitment while conferring leukemic stem cell properties. Strikingly, single transduction of BRD9-NUTM1 is sufficient to induce serially-transplantable pro-B-like leukemia in vivo, recapitulating key features of human NUTM1-r B-ALL, including NUTM1 overexpression, skewed B cell transcriptional programs, and low CD34 expression. Mechanistically, BRD9-NUTM1 expression gives rise to distinctive open chromatin regions with global enhancement of H3K27Ac, particularly at loci associated with Myc, NF-κB, and posterior Hoxa genes. Notably, BRD9-NUTM1 leukemic cells responded robustly to cytarabine, in contrast to the relative resistance observed in KMT2A-r leukemias. Interestingly, our findings highlight a discrepancy observed in the clinical behavior of NUTM1-r leukemias, where the transformed cells display characteristics of stemness, yet tend to lose these properties under chemotherapy due to the dependence on active transcription. Our findings delineate the unique molecular profile of NUTM1-r leukemias, suggesting opportunities for targeted therapies that exploit these specific vulnerabilities.
2026-04-22 | GSE276679 | GEO