Pan-cancer screen for mutations in non-coding elements with conservation and cancer specificity reveals correlations with expression and survival

Hornshøj, Henrik; Nielsen, Morten Muhlig; Sinnott‐Armstrong, Nicholas A.; Świtnicki, Michał P.; Juul, Malene; Madsen, Tobias; Sallari, Richard; Kellis, M; Ørntoft, Torben F.; Hobolth, Asger; Pedersen, Jakob Skou

doi:10.1038/s41525-017-0040-5

Cited by 70 publications

(46 citation statements)

References 80 publications

(128 reference statements)

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“…Mutations in the non-coding part of the genome constitute the "dark-matter" of cancer genomics 2 . Growing evidence indicates that many of these mutations occur in conserved motifs and loci under epigenetic control, and some of these play fundamental roles in cancer biology and disease prognosis [1][2][3][6][7][8][9] . Using WGS data produced by the ICGC, we identified dozens of recurrently mutated regulatory regions in the CLL genome.…”

Section: Discussionmentioning

confidence: 99%

Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome

Orgueira

Antelo

Arias

et al. 2020

Sci Rep

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Mutations in non-coding DNA regions are increasingly recognized as cancer drivers. These mutations can modify gene expression in cis or by inducing high-order chormatin structure modifications with long-range effects. Previous analysis reported the detection of recurrent and functional noncoding DNA mutations in the chronic lymphocytic leukemia (CLL) genome, such as those in the 3′ untranslated region of NOTCH1 and in the PAX5 super-enhancer. In this report, we used whole genome sequencing data produced by the International Cancer Genome Consortium in order to analyze regions with previously reported regulatory activity. This approach enabled the identification of numerous recurrently mutated regions that were frequently positioned in the proximity of genes involved in immune and oncogenic pathways. By correlating these mutations with expression of their nearest genes, we detected significant transcriptional changes in genes such as PHF2 and S1PR2. More research is needed to clarify the function of these mutations in CLL, particularly those found in intergenic regions. A major part of mutations in the cancer genome occur in non-coding DNA regions, and their function is still beginning to be understood 1. Non-coding DNA comprises approximately 98% of the human genome, but recent research has proven that most of these regions are either part of regulatory motifs or actively transcribed to RNA 2,3. These mutations can induce functional genomic changes by altering the binding of transcription factors or by inducing high-order chromatin structural modifications 2,4. For example, mutations in 5′ and 3′ untranslated regions (UTRs) may disturb RNA structural conformation, modify microRNA binding sites or disrupt polyadenylation signals 2. In a similar fashion, mutations affecting non-protein coding genes such as microRNA and long intergenic RNA genes (lincRNAs) are known cancer driver events 2,5. Different studies have evidenced that the expression of genes such as BRCA1, CDH10, CCND1, MALAT1, PAX5, RB1, SDHD, TERT, TOX3, and TAL1 is influenced by non-coding DNA mutations in regulatory regions of the cancer genome 1,6,7. The Pancancer Analysis of Whole Genomes (PCAWG) project has revealed the existence of common and tumor-specific recurrently mutated functional elements near known cancer drivers 7. Some of these driver mutations can induce long-range changes in genome organization and trigger abnormal expression of distant oncogenes and tumor suppressors 8. Furthermore, the sequence distribution of these driver mutations is not random. Hornshøj et al. (2018) identified a significant enrichment in conserved CCCT-binding factor (CTCF) binding sites among recurrently mutated non-coding DNA regions with cancer specificity 6. Similarly, Line et al. (2019) identified 21 recurrently altered CTCF-rich insulator regions in the cancer genome, and elegantly demonstrated that some of these mutations drive tumor proliferation 9. Chronic Lymphocytic Leukemia (CLL) is among the most frequent lymphoproliferative disorders, and it is cha...

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Section: Discussionmentioning

confidence: 99%

Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome

Orgueira

Antelo

Arias

et al. 2020

Sci Rep

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“…In the present study we established G6PD as a functional miR-122 target, and G6PD could be potential therapeutic target for HCC. Down regulation of miR-122 expression associated with or hypermethylation of upstream promoter region is predictive of poor overall survival in human liver cancer patients 18 , 29 , 37 , 42 . We find that the G6PD 3′-UTR harbors three miR-122 sites, and two are validated as functional sites (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Several groups including ours demonstrated that miR-122, a highly conserved liver-specific miRNA expressed in vertebrates 15 , is a novel tumor suppressor in HCC 16 – 18 . This small (21–23 nt) non-coding RNA regulates gene expression post-transcriptionally by mediating Argonaute binding at the target RNA sites complementary to the miR-122 seed sequence, causing decay of target message 19 .…”

Section: Introductionmentioning

confidence: 86%

The role of miR-122 in the dysregulation of glucose-6-phosphate dehydrogenase (G6PD) expression in hepatocellular cancer

Barajas

Reyes

Guerrero

et al. 2018

Sci Rep

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Thus, a better understanding of molecular aberrations involved in HCC pathogenesis is necessary for developing effective therapy. It is well established that cancer cells metabolize energy sources differently to rapidly generate biomass. Glucose-6-phosphate-dehydrogenase (G6PD), the rate-limiting enzyme of the Pentose Phosphate Pathway (PPP), is often activated in human malignancies to generate precursors for nucleotide and lipid synthesis. Here, we determined the clinical significance of G6PD in primary human HCC by analyzing RNA-seq and clinical data in The Cancer Genome Atlas. We found that the upregulation of G6PD correlates with higher tumor grade, increased tumor recurrence, and poor patient survival. Notably, liver-specific miR-122, which is essential for metabolic homeostasis, suppresses G6PD expression by directly interacting with its 3′UTR. Luciferase reporter assay confirmed two conserved functional miR-122 binding sites located in the 3′-UTR of G6PD. Furthermore, we show that ectopic expression of miR-122 and miR-1, a known regulator of G6PD expression coordinately repress G6PD expression in HCC cells. These miRNAs also reduced G6PD activity in HepG2 cells that express relatively high activity of this enzyme. Collectively, this study provides evidence that anti-HCC efficacy of miR122 and miR-1 could be mediated, at least in part, through inhibition of PPP by suppressing the expression of G6PD.

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“…Our findings also overlap previous reports in that somatic mutations in other regulatory regions of the same genes in the same type of cancer have been implicated as drivers. For example, mutations in the splice-acceptor site of GATA3 were previously implicated in LUAD 37 . Here we implicated promoter mutations in GATA3 in LUAD.…”

Section: Discussionmentioning

confidence: 99%

A catalog of cis-regulatory mutations in 12 major cancer types

Cheng

Vermeulen

Rollins-Green

et al. 2019

Preprint

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39Despite the recent availability of complete genome sequences of tumors from thousands of 40 patients, isolating disease-causing (driver) non-coding mutations from the plethora of somatic 41 variants is notoriously challenging, and only a handful of validated examples exist. By integrating 42 whole-genome sequencing, gene expression, chromatin accessibility, and genetic data from 43 TCGA, we identified 301 non-coding somatic mutations that affect gene expression in cis. These 44 mutations cluster into 36 hotspot regions with diverse molecular mechanisms of gene expression 45 regulation. We further show that these mutations have hallmark features of noncoding drivers; 46

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Pan-cancer screen for mutations in non-coding elements with conservation and cancer specificity reveals correlations with expression and survival

Cited by 70 publications

References 80 publications

Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome

Novel Mutation Hotspots within Non-Coding Regulatory Regions of the Chronic Lymphocytic Leukemia Genome

The role of miR-122 in the dysregulation of glucose-6-phosphate dehydrogenase (G6PD) expression in hepatocellular cancer

A catalog of cis-regulatory mutations in 12 major cancer types

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