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Updated: Jun 29, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma
James E Jacobs1, Lara Davis1, Shannon McWeeney1
1Oregon Health & Science University, Portland, OR, United States.
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.
Insights
Aberrations in the nuclear pore complex disassembly (NPCD) pathway correlate with poor survival in osteosarcoma, independent of MYC overexpression. This finding offers new insights into aggressive osteosarcoma and potential therapeutic targets.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Osteosarcoma is a challenging bone cancer, particularly in young patients with metastatic disease.
- Developing targeted therapies is hindered by a lack of consistent genetic markers.
- MYC overexpression is linked to poor outcomes, but other prognostic markers are needed.
Purpose of the Study:
- To identify genomic characteristics correlating with overall survival in osteosarcoma.
- To define aberrant molecular pathway signatures associated with aggressive disease.
- To explore novel genetic drivers beyond MYC in osteosarcoma.
Main Methods:
- Whole genome sequencing of 106 osteosarcoma tumors and matched controls.
- Analysis of single nucleotide variants and differential gene expression.
- Pathway enrichment analysis focusing on nuclear pore complex disassembly (NPCD) and MYC-responsive genes.
Main Results:
- Mutations in the NPCD pathway significantly correlate with poorer overall survival.
- Immune response and regulation genes are enriched in NPCD-aberrant tumors.
- Neither MYC nor MYC-responsive genes showed differential expression between NPCD-aberrant and non-aberrant groups.
- NPCD pathway mutations are predominantly regulatory variants, suggesting epigenetic dysregulation.
Conclusions:
- NPCD pathway aberrations represent a novel, MYC-independent marker of poor prognosis in osteosarcoma.
- These findings highlight the role of genetic regulatory network dysregulation in aggressive osteosarcoma.
- Identifying NPCD pathway aberrations may lead to new, personalized treatment strategies.
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