Cancer LncRNA Census 2 (CLC2): an enhanced resource reveals clinical features of cancer lncRNAs

Long noncoding RNAs play key roles in cancer and are at the vanguard of precision therapeutic development. These efforts depend on large and high-confidence collections of cancer lncRNAs. Here we present the Cancer LncRNA Census 2 (CLC2): at 492 cancer lncRNAs, it is 4-fold greater than its predecessor, without compromising on strict criteria of confident functional / genetic roles and inclusion in the GENCODE annotation scheme. This increase was enabled by leveraging high-throughput transposon insertional mutagenesis (TIM) screening data, yielding 95 novel cancer lncRNAs. CLC2 makes a valuable addition to existing collections: it is amongst the largest, holds the greatest number of unique genes, and carries functional labels (oncogene / tumour suppressor). Analysis of this dataset reveals that cancer lncRNAs are impacted by germline variants, somatic mutations, and changes in expression consistent with inferred disease functions. Furthermore, we show how clinical / genomic features can be used to vet prospective gene sets from high-throughput sources. The combination of size and quality makes CLC2 a foundation for precision medicine, demonstrating cancer lncRNAs’ evolutionary and clinical significance.

[1]  Xia Li,et al.  Lnc2Cancer 3.0: an updated resource for experimentally supported lncRNA/circRNA cancer associations and web tools based on RNA-seq and scRNA-seq data , 2020, Nucleic Acids Res..

[2]  Nuno A. Fonseca,et al.  Analyses of non-coding somatic drivers in 2,658 cancer whole genomes , 2020, Nature.

[3]  Nuno A. Fonseca,et al.  Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis , 2020, Communications Biology.

[4]  P. Drivers.  Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis , 2020 .

[5]  Mary Goldman,et al.  Genomic basis for RNA alterations in cancer , 2020, Nature.

[6]  Jun Yu,et al.  Analyses of non-coding somatic drivers in 2,658 cancer whole genomes , 2020, Nature.

[7]  Rory Johnson,et al.  CASPR, an analysis pipeline for single and paired guide RNA CRISPR screens, reveals optimal target selection for long non-coding RNAs , 2019, Bioinform..

[8]  Max A. Horlbeck,et al.  CRISPRi-based radiation modifier screen identifies long non-coding RNA therapeutic targets in glioma , 2019, Genome Biology.

[9]  Zhirui Guo,et al.  lncRNA DGCR5 Up-Regulates TGF-β1, Increases Cancer Cell Stemness and Predicts Survival of Prostate Cancer Patients , 2019, Cancer management and research.

[10]  F. Slack,et al.  The Role of Non-coding RNAs in Oncology , 2019, Cell.

[11]  Rory Johnson,et al.  LnCompare: gene set feature analysis for human long non-coding RNAs , 2019, Nucleic Acids Res..

[12]  Rory Johnson,et al.  Hacking the Cancer Genome: Profiling Therapeutically Actionable Long Non-coding RNAs Using CRISPR-Cas9 Screening. , 2019, Cancer cell.

[13]  Helen E. Parkinson,et al.  The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019 , 2018, Nucleic Acids Res..

[14]  Li Wang,et al.  Lnc2Cancer v2.0: updated database of experimentally supported long non-coding RNAs in human cancers , 2018, Nucleic Acids Res..

[15]  Mark Gerstein,et al.  GENCODE reference annotation for the human and mouse genomes , 2018, Nucleic Acids Res..

[16]  Vladimir B. Bajic,et al.  LncBook: a curated knowledgebase of human long non-coding RNAs , 2018, Nucleic Acids Res..

[17]  Zhen Yang,et al.  LncRNADisease 2.0: an updated database of long non-coding RNA-associated diseases , 2018, Nucleic Acids Res..

[18]  Jing Li,et al.  CRlncRNA: a manually curated database of cancer-related long non-coding RNAs with experimental proof of functions on clinicopathological and molecular features , 2018, BMC Medical Genomics.

[19]  C. Cole,et al.  The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers , 2018, Nature Reviews Cancer.

[20]  E. Lander,et al.  The NORAD lncRNA assembles a topoisomerase complex critical for genome stability , 2018, Nature.

[21]  A. Frankish,et al.  Towards a complete map of the human long non-coding RNA transcriptome , 2018, Nature Reviews Genetics.

[22]  N. Munshi,et al.  Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity , 2018, Leukemia.

[23]  J. Mendell,et al.  Functional Classification and Experimental Dissection of Long Noncoding RNAs , 2018, Cell.

[24]  Yaoqi Zhou,et al.  EVLncRNAs: a manually curated database for long non-coding RNAs validated by low-throughput experiments , 2017, Nucleic Acids Res..

[25]  Huynh-Hoa Bui,et al.  Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA , 2017, Cell.

[26]  Yuan Yuan,et al.  Single nucleotide polymorphisms and cancer susceptibility , 2017, Oncotarget.

[27]  I. Ulitsky,et al.  The human lncRNA LINC-PINT inhibits tumor cell invasion through a highly conserved sequence element , 2017, Genome Biology.

[28]  S. Crooke,et al.  RNase H1-Dependent Antisense Oligonucleotides Are Robustly Active in Directing RNA Cleavage in Both the Cytoplasm and the Nucleus , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[29]  Daniel G. Anderson,et al.  Advances in the delivery of RNA therapeutics: from concept to clinical reality , 2017, Genome Medicine.

[30]  Howard Y. Chang,et al.  NONCODING RNA: CRISPRi‐based genome‐scale identification of functional long noncoding RNA loci in human cells , 2017 .

[31]  Ksenia Myacheva,et al.  Challenges of CRISPR/Cas9 applications for long non-coding RNA genes , 2016, Nucleic acids research.

[32]  Jianjun Luo,et al.  LncVar: a database of genetic variation associated with long non-coding genes , 2017, Bioinform..

[33]  E. Lander,et al.  Local regulation of gene expression by lncRNA promoters, transcription and splicing , 2016, Nature.

[34]  I. Ulitsky,et al.  The functions of long noncoding RNAs in development and stem cells , 2016, Development.

[35]  J. Rinn,et al.  In Vivo Characterization of Linc-p21 Reveals Functional cis-Regulatory DNA Elements. , 2016, Cell reports.

[36]  Ferran Reverter,et al.  Discovery of Cancer Driver Long Noncoding RNAs across 1112 Tumour Genomes: New Candidates and Distinguishing Features , 2016, Scientific Reports.

[37]  A. Gonzalez-Perez,et al.  OncodriveFML: a general framework to identify coding and non-coding regions with cancer driver mutations , 2016, Genome Biology.

[38]  Stefan Van Aelst,et al.  Melanoma addiction to the long non-coding RNA SAMMSON , 2016, Nature.

[39]  Tsung-Cheng Chang,et al.  Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins , 2016, Cell.

[40]  Gianluca Bontempi,et al.  TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data , 2015, Nucleic acids research.

[41]  R. Guigó,et al.  CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis. , 2015, Journal of molecular and cellular cardiology.

[42]  Roderic Guigó,et al.  DECKO: Single-oligo, dual-CRISPR deletion of genomic elements including long non-coding RNAs , 2015, BMC Genomics.

[43]  Emma L. Koppe,et al.  In silico and in vitro evaluation of exonic and intronic off-target effects form a critical element of therapeutic ASO gapmer optimization , 2015, Nucleic acids research.

[44]  C. Haiman,et al.  Mercapturic Acids Derived from the Toxicants Acrolein and Crotonaldehyde in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer , 2015, PloS one.

[45]  S. Orkin,et al.  Opposing Roles for the lncRNA Haunt and Its Genomic Locus in Regulating HOXA Gene Activation during Embryonic Stem Cell Differentiation. , 2015, Cell stem cell.

[46]  S. Dhanasekaran,et al.  The landscape of long noncoding RNAs in the human transcriptome , 2015, Nature Genetics.

[47]  Marcel E. Dinger,et al.  lncRNAdb v2.0: expanding the reference database for functional long noncoding RNAs , 2014, Nucleic Acids Res..

[48]  Yen-Yi Ho,et al.  The Candidate Cancer Gene Database: a database of cancer driver genes from forward genetic screens in mice , 2014, Nucleic Acids Res..

[49]  R. Guigó,et al.  The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs , 2014, RNA.

[50]  D. Bartel,et al.  lincRNAs: Genomics, Evolution, and Mechanisms , 2013, Cell.

[51]  C. Wahlestedt.  Targeting long non-coding RNA to therapeutically upregulate gene expression , 2013, Nature Reviews Drug Discovery.

[52]  Zhen Su,et al.  Integrative genomic analyses reveal clinically relevant long non-coding RNA in human cancer , 2013 .

[53]  D. Spector,et al.  The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. , 2013, Cancer research.

[54]  Peter J. Campbell,et al.  Evolution of the cancer genome , 2012, Nature Reviews Genetics.

[55]  David G. Knowles,et al.  The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression , 2012, Genome research.

[56]  J. Rinn,et al.  Modular regulatory principles of large non-coding RNAs , 2012, Nature.

[57]  D. Bartel,et al.  Conserved Function of lincRNAs in Vertebrate Embryonic Development despite Rapid Sequence Evolution , 2011, Cell.

[58]  J. Castle.  SNPs Occur in Regions with Less Genomic Sequence Conservation , 2011, PloS one.

[59]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[60]  N. Copeland,et al.  Harnessing transposons for cancer gene discovery , 2010, Nature Reviews Cancer.

[61]  T. Derrien,et al.  Long Noncoding RNAs with Enhancer-like Function in Human Cells , 2010, Cell.

[62]  J. Rinn,et al.  A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response , 2010, Cell.

[63]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

[64]  Rory Johnson,et al.  Regulation of neural macroRNAs by the transcriptional repressor REST. , 2008, RNA.

[65]  Thomas D. Schmittgen,et al.  Analyzing real-time PCR data by the comparative CT method , 2008, Nature Protocols.

[66]  Desmond G. Higgins,et al.  Distinct Patterns in the Regulation and Evolution of Human Cancer Genes , 2008, Silico Biol..

[67]  David A. Lee,et al.  Predicting protein function from sequence and structure , 2007, Nature Reviews Molecular Cell Biology.

[68]  Alan M. Moses,et al.  In vivo enhancer analysis of human conserved non-coding sequences , 2006, Nature.

[69]  Christos A Ouzounis,et al.  Structural and functional properties of genes involved in human cancer , 2006, BMC Genomics.

[70]  D. Haussler,et al.  Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. , 2005, Genome research.

[71]  N. Dias,et al.  Antisense oligonucleotides: basic concepts and mechanisms. , 2002, Molecular cancer therapeutics.

[72]  M. Gerstein,et al.  Assessing annotation transfer for genomics: quantifying the relations between protein sequence, structure and function through traditional and probabilistic scores. , 2000, Journal of molecular biology.

[73]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[74]  F. Cleton.  Evolution of Cancer , 1991, British Journal of Cancer.