American Association for Cancer Research
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Figure S7 from Integrative Genomic Analyses Identify LncRNA Regulatory Networks across Pediatric Leukemias and Solid Tumors

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posted on 2023-10-13, 07:20 authored by Apexa Modi, Gonzalo Lopez, Karina L. Conkrite, Chun Su, Tsz Ching Leung, Sathvik Ramanan, Elisabetta Manduchi, Matthew E. Johnson, Daphne Cheung, Samantha Gadd, Jinghui Zhang, Malcolm A. Smith, Jaime M. Guidry Auvil, Soheil Meshinchi, Elizabeth J. Perlman, Stephen P. Hunger, John M. Maris, Andrew D. Wells, Struan F.A. Grant, Sharon J. Diskin

Figure S7: Validation of TBX2-AS1 expression in NBL cell lines and impact on NBL cell growth

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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National Human Genome Research Institute (NHGRI)

United States Department of Health and Human Services

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Children's Oncology Group (COG)

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ARTICLE ABSTRACT

Long noncoding RNAs (lncRNA) 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 curated RNA sequencing data for 1,044 pediatric leukemia and extracranial solid tumors and integrated paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. A total of 2,657 lncRNAs were robustly expressed across six pediatric cancers, including 1,142 exhibiting histotype-elevated expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Application of a multidimensional 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-elevated and developmental lncRNAs. Integration of these analyses prioritized lncRNAs for experimental validation, and silencing of TBX2-AS1, the top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells, confirming the 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. Comprehensive characterization of lncRNAs in pediatric cancer leads to the identification of highly expressed lncRNAs across childhood cancers, annotation of lncRNAs showing histotype-specific elevated expression, and prediction of lncRNA gene regulatory networks.

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