Pan-cancer analysis of non-coding transcripts reveals the prognostic onco-lncRNA HOXA10-AS in gliomas
Keren Isaev,
Lingyan Jiang,
Shuai Wu,
Christian A. Lee,
Valérie Watters,
Victoire Fort,
Ricky Tsai,
Fiona J. Coutinho,
Samer M.I. Hussein,
Jie Zhang,
Jinsong Wu,
Peter B. Dirks,
Daniel Schramek,
Jüri Reimand
Affiliations
Keren Isaev
Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
Lingyan Jiang
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
Shuai Wu
Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China
Christian A. Lee
Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
Valérie Watters
Cancer Research Center, Université Laval, Quebec City, QC, Canada; CHU of Québec-Université Laval Research Center, Oncology Division, Quebec City, QC, Canada
Victoire Fort
Cancer Research Center, Université Laval, Quebec City, QC, Canada; CHU of Québec-Université Laval Research Center, Oncology Division, Quebec City, QC, Canada
Ricky Tsai
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
Fiona J. Coutinho
SickKids Research Institute, Toronto, ON, Canada
Samer M.I. Hussein
Cancer Research Center, Université Laval, Quebec City, QC, Canada; CHU of Québec-Université Laval Research Center, Oncology Division, Quebec City, QC, Canada
Jie Zhang
Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China
Jinsong Wu
Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China
Peter B. Dirks
SickKids Research Institute, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
Daniel Schramek
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Corresponding author
Jüri Reimand
Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Corresponding author
Summary: Long non-coding RNAs (lncRNAs) are increasingly recognized as functional units in cancer and powerful biomarkers; however, most remain uncharacterized. Here, we analyze 5,592 prognostic lncRNAs in 9,446 cancers of 30 types using machine learning. We identify 166 lncRNAs whose expression correlates with survival and improves the accuracy of common clinical variables, molecular features, and cancer subtypes. Prognostic lncRNAs are often characterized by switch-like expression patterns. In low-grade gliomas, HOXA10-AS activation is a robust marker of poor prognosis that complements IDH1/2 mutations, as validated in another retrospective cohort, and correlates with developmental pathways in tumor transcriptomes. Loss- and gain-of-function studies in patient-derived glioma cells, organoids, and xenograft models identify HOXA10-AS as a potent onco-lncRNA that regulates cell proliferation, contact inhibition, invasion, Hippo signaling, and mitotic and neuro-developmental pathways. Our study underscores the pan-cancer potential of the non-coding transcriptome for identifying biomarkers and regulators of cancer progression.
