@misc{10481/84877,
year = {2023},
month = {6},
url = {https://hdl.handle.net/10481/84877},
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 positivelyselected
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.},
organization = {Swiss National Science Foundation through the National Centre of Competence in Research (NCCR) "RNA amp; Disease"	51NF40-182880},
organization = {The elements of long noncoding RNA function	31003A_182337},
organization = {Sinergia project "Regenerative strategies for heart disease via targeting the long noncoding transcriptome"	173738},
organization = {Medical Faculty of the University and University Hospital of Bern},
organization = {Helmut Horten Stiftung, Swiss Cancer Research Foundation	4534-08-2018},
organization = {Science Foundation Ireland	18/FRL/6194
18/CRT/6214},
publisher = {Springer Nature},
title = {Tumour mutations in long noncoding RNAs enhance cell fitness},
doi = {10.1038/s41467-023-39160-7},
author = {Esposito, Roberta and Andrades Delgado, Álvaro},
}