RT Journal Article
SR Electronic
T1 Tumour mutations in long noncoding RNAs enhance cell fitness
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.06.467555
DO 10.1101/2021.11.06.467555
A1 Roberta Esposito
A1 Andrés Lanzós
A1 Taisia Polidori
A1 Hugo Guillen-Ramirez
A1 Bernard Mefi Merlin
A1 Lia Mela
A1 Eugenio Zoni
A1 Isabel Büchi
A1 Lusine Hovhannisyan
A1 Finn McCluggage
A1 Matúš Medo
A1 Giulia Basile
A1 Dominik F. Meise
A1 Sunandini Ramnarayanan
A1 Sandra Zwyssig
A1 Corina Wenger
A1 Kyriakos Schwarz
A1 Adrienne Vancura
A1 Núria Bosch-Guiteras
A1 Marianna Kruithof-de Julio
A1 Yitzhak Zimmer
A1 Michaela Medová
A1 Deborah Stroka
A1 Archa Fox
A1 Rory Johnson
YR 2022
UL http://biorxiv.org/content/early/2022/07/28/2021.11.06.467555.abstract
AB Long noncoding RNAs (lncRNAs) can act as tumour suppressors or oncogenes to repress/promote tumour cell proliferation via RNA-dependent mechanisms. Recently, genome sequencing has identified elevated densities of tumour somatic single nucleotide variants (SNVs) in lncRNA genes. However, this has been attributed to phenotypically-neutral “passenger” processes, and the existence of positively-selected fitness-altering “driver” SNVs acting via lncRNAs has not been addressed. We developed and used ExInAtor2, an improved driver-discovery pipeline, to map pancancer and cancer-specific mutated lncRNAs across an extensive cohort of 2583 primary and 3527 metastatic tumours. The 54 resulting lncRNAs are mostly linked to cancer for the first time. Their significance is supported by a range of clinical and genomic evidence, and display oncogenic potential when experimentally expressed in matched tumour models. Our results revealed a striking SNV hotspot in the iconic NEAT1 oncogene, which was ascribed by previous studies to passenger processes. To directly evaluate the functional significance of NEAT1 SNVs, we used in cellulo mutagenesis to introduce tumour-like mutations in the gene and observed a consequent increase in cell proliferation in both transformed and normal backgrounds. Mechanistic analyses revealed that SNVs alter NEAT1 ribonucleoprotein assembly and boost subnuclear paraspeckles. This is the first experimental evidence that mutated lncRNAs can contribute to the pathological fitness of tumour cells.Competing Interest StatementThe authors have declared no competing interest.