Frequent lncRNA-derived fusions in pediatric neuroblastoma identified by LncFusion: potential biomarker and therapeutic implications

Despite growing interest in the onco-fusion proteins and long noncoding RNAs (lncRNAs) in cancers, lncRNA-derived fusion transcripts in pediatric cancers remain understudied. To address this gap, we first developed LncFusion, a novel computational pipeline that systematically detects lncRNA-derived fusion transcripts from RNA-seq data. Leveraging our previously published Flnc (for comprehensive lncRNA identification) as a foundation and applying LncFusion, we identified over 900 high-confidence lncRNA-derived fusions (lnc-fusions) in pediatric neuroblastoma by analyzing the transcriptomics datasets from three major pediatric cancer cohorts--TARGET, Gabriella Miller Kids First, and St. Jude Cloud. The number of lnc-fusions exceeds the number of mRNA-derived fusions (mRNA-fusions) in neuroblastoma. Whole genome sequencing analyses revealed that approximately 40% of these lnc-fusions result from chromosomal rearrangements, while over 60% may arise from aberrant splicing events. Among these high-confidence lnc-fusions, 61 are enriched in pediatric neuroblastoma compared to healthy controls; and 20s exhibit subtype-specific expressions in pediatric neuroblastoma patients, which would be categorized into three groups: MYCN-amplified patients, c-MYC-highly expressed patients and the remaining (MYCN-unamplified and c-MYC not high expression). Subtype-specific enrichment of certain lnc-fusions, particularly in MYCN-amplified and c-MYC-high subgroups, underscores distinct oncogenic roles. Further functional studies implicated lnc-fusions in key pathways related to neuron development, translation, and energy metabolism, suggesting potential contributions to neuroblastoma pathogenesis. Additionally, We found several novel fusions might serve as potential diagnostic or prognostic biomarkers in neuroblastoma. A few candidates correlate with either favorable histology and lower-risk patient subsets, or poorer survival outcomes, indicating strong prognostic biomarker potential. Experiments in cell line further confirmed the presence of a few key lnc-fusions discovered from patient samples. Our findings provide the first comprehensive insight into lncRNA-derived fusions in pediatric neuroblastoma, providing the promise of lnc-fusions as novel biomarkers and therapeutic targets. The LncFusion tool developed can also be applied to explore lnc-fusions in other pediatric and adult cancers.