Integrative Genomic Analyses Identify LncRNA Regulatory Networks across Pediatric Leukemias and Solid Tumors

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

doi:10.1158/0008-5472.CAN-22-3186

Integrative Genomic Analyses Identify LncRNA Regulatory Networks across Pediatric Leukemias and Solid Tumors

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Pages (from-to)	3462-3477
Number of pages	16
Journal	Cancer Research
Volume	83
Issue number	20
DOIs	https://doi.org/10.1158/0008-5472.CAN-22-3186
State	Published - Oct 15 2023

Funding

This work was supported in part by NIH grants R01-CA124709 (S.J. Diskin), R01-CA237562 (S.J. Diskin), R03-CA230366 (S.J. Diskin), X01-HL136997 (J.M. Maris), and T32-HG46–18 (A. Modi). This project was also funded in part by a supplement to the Children’s Oncology Group Chair’s grant CA098543 and with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E to S.J. Diskin, and Complete Genomics. Promoter Capture C studies were partially funded by the Center for Spatial and Functional Genomics (A.D. Wells and S.F.A. Grant) at CHOP. S.F.A. Grant was supported by the Daniel B. Burke Endowed and Chair for Diabetes Research and R01 HG010067. The authors thank Dr. Daniela S. Gerhard for her leadership and steadfast commitment to childhood cancer research, including the TARGET project. Dr. Gerhard collaborated on this study and provided important feedback on the initial manuscript draft prior to her passing on June 25, 2021. The authors also thank Dr. Jo Lynne Rokita and Dr. Amber Weiner for insightful discussions that contributed to this project.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-22-3186

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Modi, A., Lopez, G., Conkrite, K. L., Su, C., Leung, T. C., Ramanan, S., Manduchi, E., Johnson, M. E., Cheung, D., Gadd, S., Zhang, J., Smith, M. A., Guidry Auvil, J. M., Meshinchi, S., Perlman, E. J., Hunger, S. P., Maris, J. M., Wells, A. D., Grant, S. F. A., & Diskin, S. J. (2023). Integrative Genomic Analyses Identify LncRNA Regulatory Networks across Pediatric Leukemias and Solid Tumors. Cancer Research, 83(20), 3462-3477. https://doi.org/10.1158/0008-5472.CAN-22-3186

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title = "Integrative Genomic Analyses Identify LncRNA Regulatory Networks across Pediatric Leukemias and Solid Tumors",

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.",

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Modi, A, Lopez, G, Conkrite, KL, Su, C, Leung, TC, Ramanan, S, Manduchi, E, Johnson, ME, Cheung, D, Gadd, S, Zhang, J, Smith, MA, Guidry Auvil, JM, Meshinchi, S, Perlman, EJ, Hunger, SP, Maris, JM, Wells, AD, Grant, SFA & Diskin, SJ 2023, 'Integrative Genomic Analyses Identify LncRNA Regulatory Networks across Pediatric Leukemias and Solid Tumors', Cancer Research, vol. 83, no. 20, pp. 3462-3477. https://doi.org/10.1158/0008-5472.CAN-22-3186

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AU - Modi, Apexa

AU - Lopez, Gonzalo

AU - Conkrite, Karina L.

AU - Su, Chun

AU - Leung, Tsz Ching

AU - Ramanan, Sathvik

AU - Manduchi, Elisabetta

AU - Johnson, Matthew E.

AU - Cheung, Daphne

AU - Gadd, Samantha

AU - Zhang, Jinghui

AU - Smith, Malcolm A.

AU - Guidry Auvil, Jaime M.

AU - Meshinchi, Soheil

AU - Perlman, Elizabeth J.

AU - Hunger, Stephen P.

AU - Maris, John M.

AU - Wells, Andrew D.

AU - Grant, Struan F.A.

AU - Diskin, Sharon J.

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Integrative Genomic Analyses Identify LncRNA Regulatory Networks across Pediatric Leukemias and Solid Tumors

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UN SDGs

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