Esposito, Roberta; Lanzós, Andrés; Uroda, Tina; Ramnarayanan, Sunandini; Büchi, Isabel; Polidori, Taisia; Guillen-Ramirez, Hugo; Mihaljevic, Ante; Merlin, Bernard Mefi; Lia, Mela; Zoni, Eugenio; Hovhannisyan, Lusine; McCluggage, Finn; Medo, Matúš; Basile, Giulia; Meise, Dominik F; Zwyssig, Sandra; Wenger, Corina; Schwarz, Kyriakos; Vancura, Adrienne; ... (2023). Tumour mutations in long noncoding RNAs enhance cell fitness. Nature communications, 14(1), p. 3342. Nature Publishing Group 10.1038/s41467-023-39160-7
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s41467-023-39160-7.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (3MB) | Preview |
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.
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