Tumour mutations in long noncoding RNAs enhance cell fitness

Abstract

Long noncoding RNAs (lncRNAs) are linked to cancer via pathogenic changes in their expression levels. Yet, it remains unclear whether lncRNAs can also impact tumour cell fitness via function-altering somatic “driver” mutations. To search for such driver-lncRNAs, we here perform a genome-wide analysis of fitness-altering single nucleotide variants (SNVs) across a cohort of 2583 primary and 3527 metastatic tumours. The resulting 54 mutated and positively-selected lncRNAs are significantly enriched for previously-reported cancer genes and a range of clinical and genomic features. A number of these lncRNAs promote tumour cell proliferation when overexpressed in in vitro models. Our results also highlight a dense SNV hotspot in the widely-studied NEAT1 oncogene. To directly evaluate the functional significance of NEAT1 SNVs, we use in cellulo mutagenesis to introduce tumour-like mutations in the gene and observe a significant and reproducible increase in cell fitness, both in vitro and in a mouse model. Mechanistic studies reveal that SNVs remodel the NEAT1 ribonucleoprotein and boost subnuclear paraspeckles. In summary, this work demonstrates the utility of driver analysis for mapping cancer-promoting lncRNAs, and provides experimental evidence that somatic mutations can act through lncRNAs to enhance pathological cancer cell fitness.

CADTAD: CAncer Driver Topologically Associated Domains identify oncogenic and tumor suppressive lncRNAs

“…The current methods for discovering CDLs have primarily remained at the level of CRLs, lacking the specificity to differentiate their precise roles in either promoting or inhibiting cancer progression. Second, the identification of driver lncRNAs based on genomic characteristics has yielded relatively low numbers 37,48,49 . To address this, we advocate approaching CDLs from a distinct perspective, one that is different from the paradigm of cancer driver protein-coding genes.…”

“…This is achieved by estimating the cumulative functional impact bias of somatic mutations within tumors, using signals of positive selection as a guiding principle. Furthermore, ExInAtor1/2 37,49 provides a framework to identify driver lncRNAs by discerning driver mutations within them. This identification is rooted in the detection of signals of positive selection that act on somatic mutations, thereby considering the mutational burden and functional impact.…”

“…RefLnc 58 was used to supplement the TCGA (PRAD, STAD, LUSC, and LUAD) and GTEx projects with combined FPKM data to obtain the expression of 26494 lncRNAs and 19490 coding genes in a single cancer type. The 17 driver lncRNAs identified by ExInAtor2 were from a publication 37 .…”

Long Non-Coding RNAs as “MYC Facilitators”

“…Examples of such advances include GRID-seq, RADICL-1-seq, and RIC-seq [ 60 , 61 , 62 , 63 ]. Purely computational methods have also been applied, revealing insightful correlations [ 64 , 65 , 66 ].…”

Multi-Omics Mining of lncRNAs with Biological and Clinical Relevance in Cancer

“…From an omics and bioinformatics point of view, we can broadly classify the approaches that have been developed to prioritize lncRNAs with a possible association with cancer into at least two categories: (1) an early integrative analysis of somatic variants with cancer driver potential that have an impact on the functional activity of lncRNAs associated with prognosis in cancer patients [37,38,[69][70][71], and (2) post-analysis integration strategies centered on the relationship between genome instability and lncRNAs with aberrant expressions associated with tumor prognosis [39][40][41][42][43][44][45] (Figure 2). A representative study was conducted to evaluate the potential impact of somatic mutations in human lncRNAs (denominated MutLncs) and their functional significance in cancer, interrogate the mutation profiles in genomic regions harboring lncRNA and their vicinity across 17 cancer types, and use an integrative pipeline to describe the significance of the MutLncs contribution to cancer [69].…”