Nature Communications (Jun 2023)
Tumour mutations in long noncoding RNAs enhance cell fitness
- Roberta Esposito,
- Andrés Lanzós,
- Tina Uroda,
- Sunandini Ramnarayanan,
- Isabel Büchi,
- Taisia Polidori,
- Hugo Guillen-Ramirez,
- Ante Mihaljevic,
- Bernard Mefi Merlin,
- Lia Mela,
- Eugenio Zoni,
- Lusine Hovhannisyan,
- Finn McCluggage,
- Matúš Medo,
- Giulia Basile,
- Dominik F. Meise,
- Sandra Zwyssig,
- Corina Wenger,
- Kyriakos Schwarz,
- Adrienne Vancura,
- Núria Bosch-Guiteras,
- Álvaro Andrades,
- Ai Ming Tham,
- Michaela Roemmele,
- Pedro P. Medina,
- Adrian F. Ochsenbein,
- Carsten Riether,
- Marianna Kruithof-de Julio,
- Yitzhak Zimmer,
- Michaela Medová,
- Deborah Stroka,
- Archa Fox,
- Rory Johnson
Affiliations
- Roberta Esposito
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Andrés Lanzós
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Tina Uroda
- School of Biology and Environmental Science, University College Dublin
- Sunandini Ramnarayanan
- School of Biology and Environmental Science, University College Dublin
- Isabel Büchi
- Department for BioMedical Research, University of Bern
- Taisia Polidori
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Hugo Guillen-Ramirez
- School of Biology and Environmental Science, University College Dublin
- Ante Mihaljevic
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Bernard Mefi Merlin
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Lia Mela
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Eugenio Zoni
- Department for BioMedical Research, University of Bern
- Lusine Hovhannisyan
- Department for BioMedical Research, University of Bern
- Finn McCluggage
- School of Molecular Sciences, University of Western Australia
- Matúš Medo
- Department for BioMedical Research, University of Bern
- Giulia Basile
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Dominik F. Meise
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Sandra Zwyssig
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Corina Wenger
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Kyriakos Schwarz
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Adrienne Vancura
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Núria Bosch-Guiteras
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Álvaro Andrades
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government
- Ai Ming Tham
- School of Biology and Environmental Science, University College Dublin
- Michaela Roemmele
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Pedro P. Medina
- GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government
- Adrian F. Ochsenbein
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Carsten Riether
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- Marianna Kruithof-de Julio
- Department for BioMedical Research, University of Bern
- Yitzhak Zimmer
- Department for BioMedical Research, University of Bern
- Michaela Medová
- Department for BioMedical Research, University of Bern
- Deborah Stroka
- Department for BioMedical Research, University of Bern
- Archa Fox
- School of Molecular Sciences, University of Western Australia
- Rory Johnson
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern
- DOI
- https://doi.org/10.1038/s41467-023-39160-7
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 21
Abstract
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.
