4.7 Article

Unraveling Gene Fusions for Drug Repositioning in High-Risk Neuroblastoma

期刊

FRONTIERS IN PHARMACOLOGY
卷 12, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.608778

关键词

neuroblastoma; structural variants; gene fusions; next-generation sequencing; drug repositioning; precision medicine 3

资金

  1. National Center for Toxicological Research (NCTR) of the U.S. Food and Drug Administration (FDA) through the Oak Ridge Institute for Science and Education (ORISE)

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This study investigated the translational ability of gene fusions for patient stratification and treatment development for high-risk neuroblastoma patients. Gene fusion profiles could be utilized to redefine patient subgroups in high-risk NB, leading to improved survival curves. The study identified potential repositioning candidates for precision medicine-based drug repositioning implementation.
High-risk neuroblastoma (NB) remains a significant therapeutic challenge facing current pediatric oncology patients. Structural variants such as gene fusions have shown an initial promise in enhancing mechanistic understanding of NB and improving survival rates. In this study, we performed a comprehensive in silico investigation on the translational ability of gene fusions for patient stratification and treatment development for high-risk NB patients. Specifically, three state-of-the-art gene fusion detection algorithms, including ChimeraScan, SOAPfuse, and TopHat-Fusion, were employed to identify the fusion transcripts in a RNA-seq data set of 498 neuroblastoma patients. Then, the 176 high-risk patients were further stratified into four different subgroups based on gene fusion profiles. Furthermore, Kaplan-Meier survival analysis was performed, and differentially expressed genes (DEGs) for the redefined high-risk group were extracted and functionally analyzed. Finally, repositioning candidates were enriched in each patient subgroup with drug transcriptomic profiles from the LINCS L1000 Connectivity Map. We found the number of identified gene fusions was increased from clinical the low-risk stage to the high-risk stage. Although the technical concordance of fusion detection algorithms was suboptimal, they have a similar biological relevance concerning perturbed pathways and regulated DEGs. The gene fusion profiles could be utilized to redefine high-risk patient subgroups with significant onset age of NB, which yielded the improved survival curves (Log-rank p value <= 0.05). Out of 48 enriched repositioning candidates, 45 (93.8%) have antitumor potency, and 24 (50%) were confirmed with either on-going clinical trials or literature reports. The gene fusion profiles have a discrimination power for redefining patient subgroups in high-risk NB and facilitate precision medicine-based drug repositioning implementation.

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