Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis

Abstract

Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.

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

“…We began with conventional manual curation of lncRNAs from the scientific literature, covering the period from January 2017 (directly after the end of the first CLC (42)) to the end of December 2018. We continued to use stringent criteria for defining cancer lncRNAs: genes must be annotated in GENCODE (here version 28), and cancer function must be demonstrated either by functional in vitro or in vivo experiments, or germline or somatic mutational evidence (see Methods) (Figure 1A).…”

“…We recently showed that some literature-curated lncRNAs were also targeted by previously-overlooked mutations in published transposon insertion mutagenesis (TIM) screens (42). We hypothesised that this insight could be extended to identify novel functional cancer lncRNAs.…”

“…Here we address this need through the creation of the Cancer LncRNA Census 2 (CLC2). It not only extends our previous CLC dataset by several fold (42), but more importantly, CLC2 takes a major step forward methodologically, by implementing an automated curation component that utilises functional evolutionary conservation for the first time. Using this data, we present a comprehensive analysis of the genomic and clinical features of cancer lncRNAs.…”

Transposable Element-Gene Splicing Modulates the Transcriptional Landscape of Human Pluripotent Stem Cells

“…In addition to their epigenetic activity, TEs are active genetically and can alter transcript splicing patterns by becoming exonised into transcripts (Macfarlan et al 2012;Wang et al 2014;Goke et al 2015;Grow et al 2015). TEs make a major contribution to the sequences of long-non-coding RNAs (lncRNAs) (Lev-Maor et al 2008;Kelley and Rinn 2012;Kapusta et al 2013;Naville et al 2016), and whilst lncRNAs have roles in normal biological processes (Goff and Rinn 2015;Bourque et al 2018;Lu et al 2020), and disease (Wapinski and Chang 2011;Carlevaro-Fita et al 2020), the roles of TEs inside the lncRNAs has received less attention. One model suggests that TEs act as functional domains within lncRNAs, something akin to globular domains of proteins (Johnson and Guigo 2014;Chishima et al 2018).…”

Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA transcripts is driven by intron retention: implications for RNA-directed therapies

“…We and others recently showed that the majority of TERT transcripts are compartmentalized in the nucleus 39,40 , suggesting a potential regulatory mechanism acting at the level of RNA. TUG1 lncRNA has a role in many cellular processes and is associated with malignancies, where it has an oncogenic role (inferred as onco-lncRNA) [41][42][43][44][45][46][47][48][49] . We and others showed that TUG1 lncRNA is located in both the nucleus and cytoplasm and, correspondingly, it was shown to have a function in both compartments 31,50,51 .…”