Integrative genomics identifies lncRNA regulatory networks across 1,044 pediatric leukemias and solid tumors

Modi, A.; Lopez, G.; Conkrite, K. L.; Leung, T. C.; Ramanan, S.; Cheung, D.; Su, C.; Manduchi, E.; Johnson, M. E.; Gadd, S.; Zhang, J.; Smith, M. A.; Guidry Auvil, J. M.; Gerhard, D. S.; Meshinchi, S.; Perlman, E. J.; Hunger, S. P.; Maris, J. M.; Wells, A. D.; Grant, S. F. A.; Diskin, S. J.

doi:10.1101/2020.12.10.420257

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bioRxiv · 10.1101/2020.12.10.420257

Integrative genomics identifies lncRNA regulatory networks across 1,044 pediatric leukemias and solid tumors

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Abstract

Long non-coding RNAs (lncRNAs) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curate RNA sequencing data for 1,044 pediatric leukemia and solid tumors and integrate paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. We report a total of 2,657 robustly expressed lncRNAs across six pediatric cancers, including 1,142 exhibiting histotype-specific expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Application of a multi-dimensional framework to identify and prioritize lncRNAs impacting gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage hallmarks. Analysis of upstream regulation via cell-type specific transcription factors further implicated distinct histotype-specific and developmental lncRNAs. We integrated our analyses to prioritize lncRNAs for experimental validation and showed that silencing of TBX2-AS1, our top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells, confirming our computational predictions. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for future mechanistic studies.

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Modi, A., Lopez, G., Conkrite, K. L., Leung, T. C., Ramanan, S., Cheung, D., Su, C., Manduchi, E., Johnson, M. E., Gadd, S., Zhang, J., Smith, M. A., Guidry Auvil, J. M., Gerhard, D. S., Meshinchi, S., Perlman, E. J., Hunger, S. P., Maris, J. M., Wells, A. D., Grant, S. F. A., Diskin, S. J.. 2020-12-11. Integrative genomics identifies lncRNA regulatory networks across 1,044 pediatric leukemias and solid tumors. https://doi.org/10.1101/2020.12.10.420257

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