Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma
Introduction:The bone tumor, osteosarcoma, remains challenging to treat in children and young adults, especially when patients present with metastatic disease. Developing new therapies based on genomic data from sequencing projects has proven difficult given the lack of recurrent genetic lesions acr...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2024.1303404/full |
| _version_ | 1797258681811730432 |
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| author | James E. Jacobs Lara Davis Shannon McWeeney |
| author_facet | James E. Jacobs Lara Davis Shannon McWeeney |
| author_sort | James E. Jacobs |
| collection | DOAJ |
| description | Introduction:The bone tumor, osteosarcoma, remains challenging to treat in children and young adults, especially when patients present with metastatic disease. Developing new therapies based on genomic data from sequencing projects has proven difficult given the lack of recurrent genetic lesions across tumors. MYC overexpression has been associated with poor outcomes in osteosarcoma. However, other genomic markers of disease severity are lacking.Materials and Methods:We utilized whole genome sequencing of 106 tumors and matched normal controls in order to define genomic characteristics that correlate with overall survival. Single nucleotide variants were overlaid onto annotated molecular pathways in order to define aberrant pathway signatures specific to aggressive osteosarcoma. Additionally, we calculated differential gene expression in a subsample of 71 tumors. Differentially expressed genes were then queried for known MYC-responsive genes.Results:Molecular pathways specific to nuclear pore complex disassembly (NPCD) show significant correlation with poor overall survival in osteosarcoma when mutations were present. Genes involved in immune response and immune regulation are enriched in the differential expression analysis of samples with and without NPCD pathway aberrations. Furthermore, neither MYC nor MYC-responsive genes show differential expression between NPCD-aberrant and non-aberrant groups. The NPCD pathway mutations are dominated by regulatory region variants rather than protein-altering mutations, suggesting that dysregulation of genetic regulatory networks may be the underlying mechanism for their relation to osteosarcoma phenotype.Discussion:Overall survival is significantly worse in patients whose tumors show aberrations in the NPCD pathway. Moreover, this difference in survival is not driven by MYC-overexpression, suggesting a novel mechanism for some aggressive osteosarcomas. These findings add light to the evolving understanding of the drivers of osteosarcoma and may aid in the search for new treatments based on patient-specific genetic data. |
| first_indexed | 2024-04-24T22:57:24Z |
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| id | doaj.art-c5af58cedd7641428bffc96b2dc6d097 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-24T22:57:24Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-c5af58cedd7641428bffc96b2dc6d0972024-03-18T04:39:16ZengFrontiers Media S.A.Frontiers in Genetics1664-80212024-03-011510.3389/fgene.2024.13034041303404Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcomaJames E. JacobsLara DavisShannon McWeeneyIntroduction:The bone tumor, osteosarcoma, remains challenging to treat in children and young adults, especially when patients present with metastatic disease. Developing new therapies based on genomic data from sequencing projects has proven difficult given the lack of recurrent genetic lesions across tumors. MYC overexpression has been associated with poor outcomes in osteosarcoma. However, other genomic markers of disease severity are lacking.Materials and Methods:We utilized whole genome sequencing of 106 tumors and matched normal controls in order to define genomic characteristics that correlate with overall survival. Single nucleotide variants were overlaid onto annotated molecular pathways in order to define aberrant pathway signatures specific to aggressive osteosarcoma. Additionally, we calculated differential gene expression in a subsample of 71 tumors. Differentially expressed genes were then queried for known MYC-responsive genes.Results:Molecular pathways specific to nuclear pore complex disassembly (NPCD) show significant correlation with poor overall survival in osteosarcoma when mutations were present. Genes involved in immune response and immune regulation are enriched in the differential expression analysis of samples with and without NPCD pathway aberrations. Furthermore, neither MYC nor MYC-responsive genes show differential expression between NPCD-aberrant and non-aberrant groups. The NPCD pathway mutations are dominated by regulatory region variants rather than protein-altering mutations, suggesting that dysregulation of genetic regulatory networks may be the underlying mechanism for their relation to osteosarcoma phenotype.Discussion:Overall survival is significantly worse in patients whose tumors show aberrations in the NPCD pathway. Moreover, this difference in survival is not driven by MYC-overexpression, suggesting a novel mechanism for some aggressive osteosarcomas. These findings add light to the evolving understanding of the drivers of osteosarcoma and may aid in the search for new treatments based on patient-specific genetic data.https://www.frontiersin.org/articles/10.3389/fgene.2024.1303404/fullosteosarcomasingle nucleotide variantsgenomic instabilitynuclear pore complexdifferential gene expressionMYC-overexpression |
| spellingShingle | James E. Jacobs Lara Davis Shannon McWeeney Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma Frontiers in Genetics osteosarcoma single nucleotide variants genomic instability nuclear pore complex differential gene expression MYC-overexpression |
| title | Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma |
| title_full | Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma |
| title_fullStr | Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma |
| title_full_unstemmed | Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma |
| title_short | Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma |
| title_sort | single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma |
| topic | osteosarcoma single nucleotide variants genomic instability nuclear pore complex differential gene expression MYC-overexpression |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2024.1303404/full |
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