TY - JOUR
T1 - Tumour mutations in long noncoding RNAs enhance cell fitness
AU - Esposito, Roberta
AU - Lanzós, Andrés
AU - Uroda, Tina
AU - Ramnarayanan, Sunandini
AU - Büchi, Isabel
AU - Polidori, Taisia
AU - Guillen-Ramirez, Hugo
AU - Mihaljevic, Ante
AU - Merlin, Bernard Mefi
AU - Mela, Lia
AU - Zoni, Eugenio
AU - Hovhannisyan, Lusine
AU - McCluggage, Finn
AU - Medo, Matúš
AU - Basile, Giulia
AU - Meise, Dominik F.
AU - Zwyssig, Sandra
AU - Wenger, Corina
AU - Schwarz, Kyriakos
AU - Vancura, Adrienne
AU - Bosch-Guiteras, Núria
AU - Andrades, Álvaro
AU - Tham, Ai Ming
AU - Roemmele, Michaela
AU - Ochsenbein, Adrian F.
AU - Riether, Carsten
AU - Kruithof-de Julio, Marianna
AU - Zimmer, Yitzhak
AU - Medová, Michaela
AU - Stroka, Deborah
AU - Fox, Archa
AU - Johnson, Rory
N1 - Funding Information:
The results shown here are based upon data generated by the TCGA, PCAWG and GTEx consortia. We thank Iñigo Martincorena (Sanger Institute) for generously providing certain data analysis scripts. We thank Federico Abascal (Sanger Institute) for generously providing cancer cell fraction data. We thank Alina Naveed (DBMR) for helpful discussions about NEAT1. We acknowledge Anne-Christine Uldry and Manfred Heller of the Mass Spectrometry and Proteomics Laboratory at the University of Bern (PMSCF) for assisting with all mass-spectrometry aspects. We thank Basak Ginsbourger (DBMR) for administrative support, and Willy Hofstetter and Patrick Furer (DBMR) for logistical support. All computation was performed on the Bern Interfaculty Bioinformatics Unit computing cluster maintained by Rémy Bruggmann and Pierre Berthier. This publication and the underlying study have been made possible partly on the basis of the data that the Hartwig Medical Foundation has made available. This work was funded by the Swiss National Science Foundation through the National Centre of Competence in Research (NCCR) “RNA & Disease” (51NF40-182880), project funding “The elements of long noncoding RNA function” (31003A_182337), Sinergia project “Regenerative strategies for heart disease via targeting the long noncoding transcriptome” (173738); by the Medical Faculty of the University and University Hospital of Bern; by the Helmut Horten Stiftung, Swiss Cancer Research Foundation (4534-08-2018); and by Science Foundation Ireland through Future Research Leaders award 18/FRL/6194. This research was also funded by Science Foundation Ireland under Grant number [18/CRT/6214] (to S.R.) and in part by the EU’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant H2020-MSCA-COFUND-2019-945385.
Funding Information:
The results shown here are based upon data generated by the TCGA, PCAWG and GTEx consortia. We thank Iñigo Martincorena (Sanger Institute) for generously providing certain data analysis scripts. We thank Federico Abascal (Sanger Institute) for generously providing cancer cell fraction data. We thank Alina Naveed (DBMR) for helpful discussions about NEAT1. We acknowledge Anne-Christine Uldry and Manfred Heller of the Mass Spectrometry and Proteomics Laboratory at the University of Bern (PMSCF) for assisting with all mass-spectrometry aspects. We thank Basak Ginsbourger (DBMR) for administrative support, and Willy Hofstetter and Patrick Furer (DBMR) for logistical support. All computation was performed on the Bern Interfaculty Bioinformatics Unit computing cluster maintained by Rémy Bruggmann and Pierre Berthier. This publication and the underlying study have been made possible partly on the basis of the data that the Hartwig Medical Foundation has made available. This work was funded by the Swiss National Science Foundation through the National Centre of Competence in Research (NCCR) “RNA & Disease” (51NF40-182880), project funding “The elements of long noncoding RNA function” (31003A_182337), Sinergia project “Regenerative strategies for heart disease via targeting the long noncoding transcriptome” (173738); by the Medical Faculty of the University and University Hospital of Bern; by the Helmut Horten Stiftung, Swiss Cancer Research Foundation (4534-08-2018); and by Science Foundation Ireland through Future Research Leaders award 18/FRL/6194. This research was also funded by Science Foundation Ireland under Grant number [18/CRT/6214] (to S.R.) and in part by the EU’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant H2020-MSCA-COFUND-2019-945385.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85161271824&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-39160-7
DO - 10.1038/s41467-023-39160-7
M3 - Article
C2 - 37291246
AN - SCOPUS:85161271824
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3342
ER -