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Cited by 542RNA regulation and diseaseRNA Research and SplicingRNA modifications and cancer

The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers

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Han, Leng, Diao, Lixia, Yu, Shuangxing, Xu, Xiaoyan, Li, Jie, Zhang, Rui, Yang, Yang, Werner, Henrica M.J. +16 more·2015·Cancer Cell
DOI 10.1016/j.ccell.2015.08.013PMC PMC4605878
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Abstract

Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions. We experimentally demonstrated the effects of several cross-tumor nonsynonymous RNA editing events on cell viability and provide the evidence that RNA editing could selectively affect drug sensitivity. These results highlight RNA editing as an exciting theme for investigating cancer mechanisms, biomarkers, and treatments.

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  • To ensure sufficient statistical power, editing sites were kept only if they had at least three edited reads in at least 3 samples and no less than 30 samples with coverage as 10 in a brain region.

    “To ensure sufficient statistical power, we only kept editing sites with at least three edited reads in at least 3 samples and no less than 30 samples with coverage as 10 in a brain region (18).”

    From Comprehensive characterization of the transcriptional landscape in Alzheimer’s disease (AD) brains (2025) · cites this paper as [18]

    The Experimental Procedures section gives both thresholds: at least three edited reads in at least three samples, followed by at least 30 samples with coverage ≥10. But it applies them per tissue or tumor type in a cancer study, not specifically in a brain region. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 45

  1. Bahn JH Lee JH Li G Greer C Peng G Xiao X Accurate identification of A-to-I RNA editing in human by transcriptome sequencing. Genome Research 2012 22 142 150 21960545 PMC3246201
  2. Bass BL RNA editing by adenosine deaminases that act on RNA. Annual Review of Biochemistry 2002 71 817 846 PMC1823043 12045112
  3. Bass BL Nishikura K Keller W Seeburg PH Emeson RB OConnell MA Samuel CE Herbert A A standardized nomenclature for adenosine deaminases that act on RNA. RNA 1997 3 947 949 9292492 PMC1369539
  4. Bazak L Haviv A Barak M Jacob-Hirsch J Deng P Zhang R Isaacs FJ Rechavi G Li JB Eisenberg E Levanon EY A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. Genome Research 2014 24 365 376 24347612 PMC3941102
  5. Carter SL Cibulskis K Helman E McKenna A Shen H Zack T Laird PW Onofrio RC Winckler W Weir BA Absolute quantification of somatic DNA alterations in human cancer. Nature Biotechnology 2012 30 413 421 PMC4383288 22544022
  6. Cenci C Barzotti R Galeano F Corbelli S Rota R Massimi L Di Rocco C O'Connell MA Gallo A Down-regulation of RNA editing in pediatric astrocytomas: ADAR2 editing activity inhibits cell migration and proliferation. The Journal of Biological Chemistry 2008 283 7251 7260 18178553
  7. Chan TH Lin CH Qi L Fei J Li Y Yong KJ Liu M Song Y Chow RK Ng VH A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma. Gut 2014 63 832 843 23766440 PMC3995272
  8. Chen CX Cho DSC Wang QD Lai F Carter KC Nishikura K A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single-and double-stranded RNA binding domains. RNA 2000 6 755 767 10836796 PMC1369955
  9. Chen LL Li Y Lin CH Chan THM Chow RKK Song YY Liu M Yuan YF Fu L Kong KL Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nature Medicine 2013 19 209 216 PMC3783260 23291631
  10. Cheung LW Yu S Zhang D Li J Ng PK Panupinthu N Mitra S Ju Z Yu Q Liang H Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. Cancer Cell 2014 26 479 494 25284480 PMC4198486
  11. Chilibeck KA Wu T Liang C Schellenberg MJ Gesner EM Lynch JM MacMillan AM FRET analysis of in vivo dimerization by RNA-editing enzymes. The Journal of Biological Chemistry 2006 281 16530 16535 16618704
  12. Cho DS Yang W Lee JT Shiekhattar R Murray JM Nishikura K Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA. The Journal of Biological Chemistry 2003 278 17093 17102 12618436
  13. Galeano F Rossetti C Tomaselli S Cifaldi L Lezzerini M Pezzullo M Boldrini R Massimi L Di Rocco CM Locatelli F Gallo A ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis. Oncogene 2013 32 998 1009 22525274 PMC3579159
  14. Gu TJ Buaas FW Simons AK Ackert-Bicknell CL Braun RE Hibbs MA Canonical A-to-I and C-to-U RNA Editing Is Enriched at 3′ UTRs and microRNA Target Sites in Multiple Mouse Tissues. PLoS One 2012 7 e33720 22448268 PMC3308996
  15. Han SW Kim HP Shin JY Jeong EG Lee WC Kim KY Park SY Lee DW Won JK Jeong SY RNA editing in RHOQ promotes invasion potential in colorectal cancer. J Exp Med 2014 211 613 621 24663214 PMC3978269
  16. Herb A Higuchi M Sprengel R Seeburg PH Q/R site editing in kainate receptor GluR5 and GluR6 pre-mRNAs requires distant intronic sequences. Proceedings of the National Academy of Sciences of the United States of America 1996 93 1875 1880 8700852 PMC39875
  17. Higuchi M Single FN Kohler M Sommer B Sprengel R Seeburg PH RNA editing of AMPA receptor subunit GluR-B: a base-paired intron-exon structure determines position and efficiency. Cell 1993 75 1361 1370 8269514
  18. Jiang Q Crews LA Barrett CL Chun HJ Court AC Isquith JM Zipeto MA Goff DJ Minden M Sadarangani A ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America 2013 110 1041 1046 23275297 PMC3549099
  19. Kawahara Y Zinshteyn B Sethupathy P Iizasa H Hatzigeorgiou AG Nishikura K Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 2007 315 1137 1140 17322061 PMC2953418
  20. Keegan LP Gallo A O'Connell MA The many roles of an RNA editor. Nat Rev Genet 2001 2 869 878 11715042
  21. Li MY Wang IX Li Y Bruzel A Richards AL Toung JM Cheung VG Widespread RNA and DNA Sequence Differences in the Human Transcriptome. Science 2011 333 53 58 21596952 PMC3204392
  22. Liang H Cheung LWT Li J Ju ZL Yu SX Stemke-Hale K Dogruluk T Lu YL Liu XP Gu C Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer. Genome Research 2012 22 2120 2129 23028188 PMC3483541
  23. Liang H Landweber LF Hypothesis: RNA editing of microRNA target sites in humans? RNA 2007 13 463 467 17255198 PMC1831856
  24. Maas S Patt S Schrey M Rich A Underediting of glutamate receptor GluR-B mRNA in malignant gliomas. Proceedings of the National Academy of Sciences of the United States of America 2001 98 14687 14692 11717408 PMC64742
  25. Maas S Rich A Changing genetic information through RNA editing. Bioessays 2000 22 790 802 10944581
  26. Martinez HD Jasavala RJ Hinkson I Fitzgerald LD Trimmer JS Kung HJ Wright ME RNA Editing of Androgen Receptor Gene Transcripts in Prostate Cancer Cells. Journal of Biological Chemistry 2008 283 29938 29949 18708348 PMC2662061
  27. Nemlich Y Greenberg E Ortenberg R Besser MJ Barshack I Jacob-Hirsch J Jacoby E Eyal E Rivkin L Prieto VG MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth. The Journal of Clinical Investigation 2013 123 2703 2718 23728176 PMC3668823
  28. Omberg L Ellrott K Yuan Y Kandoth C Wong C Kellen MR Friend SH Stuart J Liang H Margolin AA Enabling transparent and collaborative computational analysis of 12 tumor types within The Cancer Genome Atlas. Nature Genetics 2013 45 1121 1126 24071850 PMC3950337
  29. Paz N Levanon EY Amariglio N Heimberger AB Ram Z Constantini S Barbash ZS Adamsky K Safran M Hirschberg A Altered adenosine-to-inosine RNA, editing in human cancer. Genome Research 2007 17 1586 1595 17908822 PMC2045141
  30. Peng ZY Cheng YB Tan BCM Kang L Tian ZJ Zhu YK Zhang WW Liang Y Hu XD Tan XM Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome. Nature Biotechnology 2012 30 253 260 22327324
  31. Piskol R Peng ZY Wang J Li JB Lack of evidence for existence of noncanonical RNA editing. Nature Biotechnology 2013 31 19 20 23302925
  32. Qin YR Qiao JJ Chan TH Zhu YH Li FF Liu H Fei J Li Y Guan XY Chen L Adenosine-to-inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma. Cancer Research 2014 74 840 851 24302582
  33. Quayle SN Lee JY Cheung LW Ding L Wiedemeyer R Dewan RW Huang-Hobbs E Zhuang L Wilson RK Ligon KL Somatic mutations of PIK3R1 promote gliomagenesis. PloS One 2012 7 e49466 23166678 PMC3498106
  34. Ramaswami G Li JB RADAR: a rigorously annotated database of A-to-I RNA editing. Nucleic Acids Research 2014 42 D109 D113 24163250 PMC3965033
  35. Ramaswami G Lin W Piskol R Tan MH Davis C Li JB Accurate identification of human Alu and non-Alu RNA editing sites. Nature Methods 2012 9 579 581 22484847 PMC3662811
  36. Ramaswami G Zhang R Piskol R Keegan LP Deng P O'Connell MA Li JB Identifying RNA editing sites using RNA sequencing data alone. Nature Methods 2013 10 128 132 23291724 PMC3676881
  37. Rueter SM Dawson TR Emeson RB Regulation of alternative splicing by RNA editing. Nature 1999 399 75 80 10331393
  38. The Cancer Genome Atlas Research Network Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008 455 1061 1068 18772890 PMC2671642
  39. The Cancer Genome Atlas Research Network Comprehensive molecular portraits of human breast tumours. Nature 2012c 490 61 70 23000897 PMC3465532
  40. The Cancer Genome Atlas Research Network Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013a 499 43 49 23792563 PMC3771322
  41. The Cancer Genome Atlas Research Network Integrated genomic characterization of endometrial carcinoma. Nature 2013b 497 67 73 23636398 PMC3704730
  42. The Cancer Genome Atlas Research Network Weinstein JN Collisson EA Mills GB Shaw KRM Ozenberger BA Ellrott K Shmulevich I Sander C Stuart JM Network, C. G. A. R. The Cancer Genome Atlas Pan-Cancer analysis project. Nature Genetics 2013 45 1113 1120 24071849 PMC3919969
  43. Tomaselli S Galeano F Alon S Raho S Galardi S Polito VA Presutti C Vincenti S Eisenberg E Locatelli F Gallo A Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma. Genome Biology 2015 16 5 25582055 PMC4326501
  44. Wahlstedt H Daniel C Enstero M Ohman M Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. Genome Research 2009 19 978 986 19420382 PMC2694479
  45. Wang K Li M Hakonarson H ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Research 2010 38 e164 20601685 PMC2938201

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Authors
Han, L., Diao, L., Yu, S., Xu, X., Li, J., Zhang, R., Yang, Y., Werner, H. M. J., Eterovic, A. K., Yuan, Y., Li, J., Nair, N., Minelli, R., Tsang, Y. H., Cheung, L. W. T., Jeong, K. J., Roszik, J., Ju, Z., Woodman, S. E., Lu, Y., Scott, K. L., Li, J. B., Mills, G. B., & Liang, H.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Stanford University (US)
  • Baylor College of Medicine (US)
Corresponding author
  • Mills, Gordon B.
  • Liang, Han
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2015-10
Volume
28
Issue
4
Pages
515-528
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccell.2015.08.013
PMC
PMC4605878
OpenAlex
W2156538352
Cited by
542
References
4
Citations by year
2026: 22 · 2025: 34 · 2024: 54 · 2023: 70 · 2022: 59 · 2021: 71 · 2020: 59 · 2019: 45 · 2018: 42 · 2017: 51 · 2016: 27 · 2015: 8
FWCI
18.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
Funders
  • National Institutes of Health
  • University of Texas MD Anderson Cancer Center
  • National Cancer Institute (CA168394, CA 016672, P50CA098258, U01CA168394, U24CA143883, R01CA175486, P50CA083639, CA098258, P30CA016672)
  • National Institute of General Medical Sciences (R01GM102484)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords
A-to-I RNA editing, adenosine-to-inosine editing, cancer genomics, post-transcriptional modification, drug sensitivity, cell viability, tumor markers
MeSH terms
Adenosine, Antineoplastic Agents, Cell Survival, Humans, Inosine, Neoplasms, Genome, Human, RNA Editing, Cell Line, Tumor

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