Functional annotation of noncoding mutations in cancer

Umer, Husen M.; Smolinska, Karolina; Komorowski, Jan; Wadelius, Claes

doi:10.26508/lsa.201900523

Cited by 3 publications

(1 citation statement)

References 76 publications

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“…Combined with increasing awareness of the disease roles of noncoding genomic elements 6 , this naturally raises the question of whether non-protein coding mutations can also shape cancer cell fitness 7 . Growing numbers of both theoretical [8][9][10][11][12][13] and experimental studies 2,14-17 implicate noncoding SNVs in cell fitness by altering the function of elements such as enhancers, promoters, insulator elements and small RNAs 18 . Surprisingly, one important class of cancer-promoting noncoding genes has been largely overlooked: long noncoding RNAs (lncRNAs) 19 .…”

Section: Introductionmentioning

confidence: 99%

Tumour mutations in long noncoding RNAs enhance cell fitness

Esposito

Lanzós

Polidori

et al. 2021

Preprint

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Tumour DNA contains thousands of single nucleotide variants (SNVs) in non-protein-coding regions, yet it remains unclear which are “driver mutations” that promote cell fitness. Amongst the most highly mutated non-coding elements are long noncoding RNAs (lncRNAs), which can promote cancer and may be targeted therapeutically. We here searched for evidence that driver mutations may act through alteration of lncRNA function. Using an integrative driver discovery algorithm, we analysed single nucleotide variants (SNVs) from 2583 primary tumours and 3527 metastases to reveal 54 candidate “driver lncRNAs” (FDR<0.1). Their relevance is supported by enrichment for previously-reported cancer genes and by clinical and genomic features. Using knockdown and transgene overexpression, we show that tumour SNVs in two novel lncRNAs can boost cell fitness. Researchers have noted particularly high yet unexplained mutation rates in the iconic cancer lncRNA, NEAT1. We apply in cellulo mutagenesis by CRISPR-Cas9 to identify vulnerable regions of NEAT1 where SNVs reproducibly increase cell fitness in both transformed and normal backgrounds. In particular, mutations in the 5’ region of NEAT1 alter ribonucleoprotein assembly and boost the population of subnuclear paraspeckles. Together, this work reveals function-altering somatic lncRNA mutations as a new route to enhanced cell fitness during transformation and metastasis.

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Section: Introductionmentioning

confidence: 99%

Tumour mutations in long noncoding RNAs enhance cell fitness

Esposito

Lanzós

Polidori

et al. 2021

Preprint

View full text Add to dashboard Cite

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Tumour mutations in long noncoding RNAs enhance cell fitness

Esposito,

Lanzós,

Uroda

et al. 2023

Nat Commun

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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.

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Leveraging Tissue-Specific Enhancer–Target Gene Regulatory Networks Identifies Enhancer Somatic Mutations That Functionally Impact Lung Cancer

Hariprakash,

Salviato,

La Mastra

et al. 2023

Cancer Research

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Enhancers are non-coding regulatory DNA regions that modulate the transcription of target genes, often over large distances along the genomic sequence. Enhancer alterations have been associated with various pathological conditions, including cancer. However, the identification and characterization of somatic mutations in non-coding regulatory regions with a functional effect on tumorigenesis and prognosis remain a major challenge. Here we present a strategy for detecting and characterizing enhancer mutations in a genome-wide analysis of patient cohorts, across three lung cancer subtypes. Lung tissue-specific enhancers were defined by integrating experimental data and public epigenomic profiles, and the genome-wide enhancer-target gene regulatory network of lung cells was constructed by integrating chromatin 3D architecture data. Lung cancers possessed a similar mutation burden at tissue-specific enhancers and exons but with differences in their mutation signatures. Functionally relevant alterations were prioritized based on the pathway-level integration of the effect of a mutation and the frequency of mutations on individual enhancers. The genes enriched for mutated enhancers converged on the regulation of key biological processes and pathways relevant to tumor biology. Recurrent mutations in individual enhancers also impacted the expression of target genes with potential relevance for patient prognosis. Together, these findings show that non-coding regulatory mutations have a potential relevance for cancer pathogenesis and can be exploited for patient classification.

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Functional annotation of noncoding mutations in cancer

Cited by 3 publications

References 76 publications

Tumour mutations in long noncoding RNAs enhance cell fitness

Tumour mutations in long noncoding RNAs enhance cell fitness

Tumour mutations in long noncoding RNAs enhance cell fitness

Leveraging Tissue-Specific Enhancer–Target Gene Regulatory Networks Identifies Enhancer Somatic Mutations That Functionally Impact Lung Cancer

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