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

Abstract

Long non-coding RNAs (lncRNAs) play an important role in gene regulation and can 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 lncRNAs exhibiting histotype-specific expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Analysis of upstream regulation via tissue-specific, oncogenic transcription factors further implicated 608 distinct histotype-associated lncRNAs. Application of a multi-dimensional framework to identify and prioritize lncRNAs impacting entire gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage pathways. Silencing TBX2-AS1, the top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for hypothesis-driven mechanistic studies.