Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving <i>EPC2</i> and <i>GULP1</i>
Medulloblastoma is the most common malignant brain tumor in children. Immunotherapy is yet to demonstrate dramatic results in medulloblastoma, one reason being the low rate of mutations creating new antigens in this entity. In tumors with low mutational burden, gene fusions may represent a source of...
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oai:doaj.org-article:ef2a8eb1cda543319a2d2d59080d56092021-11-25T17:04:35ZIdentification of an Immunogenic Medulloblastoma-Specific Fusion Involving <i>EPC2</i> and <i>GULP1</i>10.3390/cancers132258382072-6694https://doaj.org/article/ef2a8eb1cda543319a2d2d59080d56092021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5838https://doaj.org/toc/2072-6694Medulloblastoma is the most common malignant brain tumor in children. Immunotherapy is yet to demonstrate dramatic results in medulloblastoma, one reason being the low rate of mutations creating new antigens in this entity. In tumors with low mutational burden, gene fusions may represent a source of tumor-specific neoantigens. Here, we reviewed the landscape of fusions in medulloblastoma and analyzed their predicted immunogenicity. Furthermore, we described a new in-frame fusion protein identified by RNA-Seq. The fusion involved two genes on chromosome 2 coding for the enhancer of polycomb homolog 2 (EPC2) and GULP PTB domain containing engulfment adaptor 1 (GULP1) respectively. By qRT-PCR analysis, the fusion was detected in 3 out of 11 medulloblastoma samples, whereby 2 samples were from the same patients obtained at 2 different time points (initial diagnosis and relapse), but not in other pediatric brain tumor entities. Cloning of the full-length sequence indicated that the fusion protein contains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 and the coiled-coil domain of GULP1. In silico analyses predicted binding of the neoantigen-derived peptide to HLA-A*0201. A total of 50% of the fusions described in the literature were also predicted to produce an immunogenic peptide. The EPC2-GULP1 fusion peptide was able to induce a de novo T cell response characterized by interferon gamma release of CD8<sup>+</sup> cytotoxic T cells in vitro. While the functional relevance of this fusion in medulloblastoma biology remains to be clarified, our data support an immunotherapeutic approach for pediatric medulloblastoma patients carrying the <i>EPC2-GULP1</i> fusion and other immunogenic fusions.Claudia ParetNadine LehmannHannah BenderMaximilian SprangClemens J. SommerDenis CanaLarissa SeidmannArthur WingerterMarie A. NeuKhalifa El MalkiFrancesca AltLea RothFederico MariniMalte OttenhausenMartin GlaserMarkus KnufAlexandra RussoJoerg FaberMDPI AGarticlemedulloblastomaEPC2GULP1fusionNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5838, p 5838 (2021) |
| institution |
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DOAJ |
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EN |
| topic |
medulloblastoma EPC2 GULP1 fusion Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
medulloblastoma EPC2 GULP1 fusion Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Claudia Paret Nadine Lehmann Hannah Bender Maximilian Sprang Clemens J. Sommer Denis Cana Larissa Seidmann Arthur Wingerter Marie A. Neu Khalifa El Malki Francesca Alt Lea Roth Federico Marini Malte Ottenhausen Martin Glaser Markus Knuf Alexandra Russo Joerg Faber Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving <i>EPC2</i> and <i>GULP1</i> |
| description |
Medulloblastoma is the most common malignant brain tumor in children. Immunotherapy is yet to demonstrate dramatic results in medulloblastoma, one reason being the low rate of mutations creating new antigens in this entity. In tumors with low mutational burden, gene fusions may represent a source of tumor-specific neoantigens. Here, we reviewed the landscape of fusions in medulloblastoma and analyzed their predicted immunogenicity. Furthermore, we described a new in-frame fusion protein identified by RNA-Seq. The fusion involved two genes on chromosome 2 coding for the enhancer of polycomb homolog 2 (EPC2) and GULP PTB domain containing engulfment adaptor 1 (GULP1) respectively. By qRT-PCR analysis, the fusion was detected in 3 out of 11 medulloblastoma samples, whereby 2 samples were from the same patients obtained at 2 different time points (initial diagnosis and relapse), but not in other pediatric brain tumor entities. Cloning of the full-length sequence indicated that the fusion protein contains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 and the coiled-coil domain of GULP1. In silico analyses predicted binding of the neoantigen-derived peptide to HLA-A*0201. A total of 50% of the fusions described in the literature were also predicted to produce an immunogenic peptide. The EPC2-GULP1 fusion peptide was able to induce a de novo T cell response characterized by interferon gamma release of CD8<sup>+</sup> cytotoxic T cells in vitro. While the functional relevance of this fusion in medulloblastoma biology remains to be clarified, our data support an immunotherapeutic approach for pediatric medulloblastoma patients carrying the <i>EPC2-GULP1</i> fusion and other immunogenic fusions. |
| format |
article |
| author |
Claudia Paret Nadine Lehmann Hannah Bender Maximilian Sprang Clemens J. Sommer Denis Cana Larissa Seidmann Arthur Wingerter Marie A. Neu Khalifa El Malki Francesca Alt Lea Roth Federico Marini Malte Ottenhausen Martin Glaser Markus Knuf Alexandra Russo Joerg Faber |
| author_facet |
Claudia Paret Nadine Lehmann Hannah Bender Maximilian Sprang Clemens J. Sommer Denis Cana Larissa Seidmann Arthur Wingerter Marie A. Neu Khalifa El Malki Francesca Alt Lea Roth Federico Marini Malte Ottenhausen Martin Glaser Markus Knuf Alexandra Russo Joerg Faber |
| author_sort |
Claudia Paret |
| title |
Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving <i>EPC2</i> and <i>GULP1</i> |
| title_short |
Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving <i>EPC2</i> and <i>GULP1</i> |
| title_full |
Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving <i>EPC2</i> and <i>GULP1</i> |
| title_fullStr |
Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving <i>EPC2</i> and <i>GULP1</i> |
| title_full_unstemmed |
Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving <i>EPC2</i> and <i>GULP1</i> |
| title_sort |
identification of an immunogenic medulloblastoma-specific fusion involving <i>epc2</i> and <i>gulp1</i> |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/ef2a8eb1cda543319a2d2d59080d5609 |
| work_keys_str_mv |
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| _version_ |
1718412749388644352 |