Tumour mutations in long noncoding RNAs enhance cell fitness

Long noncoding RNAs (lncRNAs) have been widely linked to cancer via pathogenic changes in their expression levels. Yet, it remains unclear whether lncRNAs could also impact tumour cell fitness via function-altering somatic driver mutations. To search for such driver-lncRNAs, we performed a genome-wide analysis of fitness-altering single nucleotide variants (SNVs) across an extensive cohort of 2583 primary and 3527 metastatic tumours. The resulting mutated and positively-selected lncRNAs are significantly enrichment 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 striking SNV hotspot in the iconic 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 observed a significant and reproducible increase in cell fitness, both in vitro and in a mouse model. Mechanistic studies revealed 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 the first experimental evidence that somatic mutations can act through lncRNAs to enhance the pathological cancer phenotypes.