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

Abstract

Long noncoding RNAs (lncRNAs) can promote or repress the cellular hallmarks of cancer.Understanding their molecular roles and realising their therapeutic potential depend on highquality catalogues of cancer lncRNA genes. Presently, such catalogues depend on labourintensive curation of heterogeneous data with permissive criteria, resulting in unknown numbers of genes without direct functional evidence. Here, we present an approach for semiautomated curation focused exclusively on pathogenic functionality. The result is Cancer LncRNA Census 2 (CLC2), comprising 492 gene loci in 33 cancer types. To complement manual literature curation, we develop an automated pipeline, CLIO-TIM, to identify novel cancer lncRNAs based on functional evolutionary conservation with mouse. This yields 95 novel lncRNAs, which display characteristics of known cancer genes and include LINC00570 (ncRNA-a5), which we demonstrate experimentally to promote cell proliferation. The clinical importance and curation accuracy of CLC2 lncRNAs is highlighted by a range of features, including evolutionary selection, expression in tumours, and both somatic and germline polymorphisms. The entire dataset is available in a highly-curated format facilitating the widest range of downstream applications. In summary, we show how manual and automated methods can be integrated to catalogue known and novel functional cancer lncRNAs with unique genomic and clinical properties.

Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities

“…By isolating cells with rapid or slow migration through a porous membrane for 48h (Figures 2c and S2f), we screened for migration-promoting lncRNAs. This yielded 98 lncRNAs, of which seven were already associated with migration and invasion in numerous cancer types (11), including NORAD, DANCR and SNHG29 (52)(53)(54)(55). These data, summarized in Figure 2h and File S2, represent a resource of functional lncRNAs in NSCLC hallmarks.…”

“…The code is available at https://github.com/RescueGum/TargetPP. Enrichment scores and nominal P-values (GSEA simulation, n=10,000) of positive and neutral control genes were used as indication for the quality of the ranking, as well as fraction of detected genes previously linked to lung cancer (11). Positive and neutral control genes were also used as "true positives/false negatives" and "false positives/true negatives" respectively to calculate ROC curves and associated statistical metrics.…”

“…A fertile source for new therapeutic targets is long noncoding RNAs (lncRNAs), with a population likely to exceed 100,000, of which >98% remain uncharacterised (7)(8)(9)(10). Hundreds of lncRNAs have been implicated in disease hallmarks across cancer types via a variety of mechanisms (11)(12)(13)(14). Examples such as SAMMSON (melanoma) and lncGRS-1 (glioma) have attracted attention as drug targets, thanks to tumour cells' potent and specific sensitivity to their inhibition via antisense oligonucleotide (ASO) therapies (15,16).…”

Tumour mutations in long noncoding RNAs enhance cell fitness

“…We extracted all Gencode ENSG identifiers, resulting in a list of 703 genes. For lncRNAs we used the second version of the Cancer LncRNA Census (Vancura et al, 2021), which contains 521 Gencode lncRNAs.…”

“…C) A filtered lncRNA gene annotation was prepared, and combined with a set of curated cancer lncRNAs from the Cancer LncRNA Census (Vancura et al, 2021). A) "Oncoplot" overview of driver lncRNA analysis in PCAWG primary tumours.…”