title: ADAR-Mediated RNA Editing Predicts Progression and Prognosis of Gastric Cancer.
abstract: Gastric cancer (GC) is the third leading cause of global cancer mortality. Adenosine-to-inosine RNA editing is a recently described novel epigenetic mechanism involving sequence alterations at the RNA but not DNA level, primarily mediated by ADAR (adenosine deaminase that act on RNA) enzymes. Emerging evidence suggests a role for RNA editing and ADARs in cancer, however, the relationship between RNA editing and GC development and progression remains unknown.
  
  
  
  In this study, we leveraged on the next-generation sequencing transcriptomics to demarcate the GC RNA editing landscape and the role of ADARs in this deadly malignancy.
  
  
  
  Relative to normal gastric tissues, almost all GCs displayed a clear RNA misediting phenotype with ADAR1/2 dysregulation arising from the genomic gain and loss of the ADAR1 and ADAR2 gene in primary GCs, respectively. Clinically, patients with GCs exhibiting ADAR1/2 imbalance demonstrated extremely poor prognoses in multiple independent cohorts. Functionally, we demonstrate in vitro and in vivo that ADAR-mediated RNA misediting is closely associated with GC pathogenesis, with ADAR1 and ADAR2 playing reciprocal oncogenic and tumor suppressive roles through their catalytic deaminase domains, respectively. Using an exemplary target gene PODXL (podocalyxin-like), we demonstrate that the ADAR2-regulated recoding editing at codon 241 (His to Arg) confers a loss-of-function phenotype that neutralizes the tumorigenic ability of the unedited PODXL.
  
  
  
  Our study highlights a major role for RNA editing in GC disease and progression, an observation potentially missed by previous next-generation sequencing analyses of GC focused on DNA alterations alone. Our findings also suggest new GC therapeutic opportunities through ADAR1 enzymatic inhibition or the potential restoration of ADAR2 activity.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Tim Hon Man
authors.initials: TH
authors.lastname: Chan
authors.affiliation: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Aditi
authors.initials: A
authors.lastname: Qamra
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Kar Tong
authors.initials: KT
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Lihua
authors.initials: L
authors.lastname: Qi
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Jaymie Siqi
authors.initials: JS
authors.lastname: Lin
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Vanessa Hui En
authors.initials: VH
authors.lastname: Ng
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Huiqi
authors.initials: H
authors.lastname: Hong
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Su Ting
authors.initials: ST
authors.lastname: Tay
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore; Singapore-Massachusetts Institute of Technology Alliance, Singapore.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Yonsei Cancer Center, Seodaemun-gu, Seoul, South Korea.
authors.forename: Sun Yong
authors.initials: SY
authors.lastname: Rha
authors.affiliation: Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jimmy Bok Yan
authors.initials: JB
authors.lastname: So
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore; Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Gastroenterology and Hepatology, National University Health System, Singapore.
authors.forename: Khay Guan
authors.initials: KG
authors.lastname: Yeoh
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore; Centre for Computational Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Steve
authors.initials: S
authors.lastname: Rozen
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore; Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore; Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore; Cellular and Molecular Research, National Cancer Centre, Singapore; Genome Institute of Singapore, Singapore. Electronic address: gmstanp@duke-nus.edu.sg.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: csicl@nus.edu.sg.
authors.forename: Leilei
authors.initials: L
authors.lastname: Chen
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics*; D003062:Codon; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D017393:RNA Editing; D016601:RNA-Binding Proteins / Q000235:genetics*; D017423:Sequence Analysis, RNA; D012795:Sialoglycoproteins / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome
chemical_list: D003062:Codon; D016601:RNA-Binding Proteins; D012795:Sialoglycoproteins; C001643:podocalyxin; C000595356:ADAR protein, human; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase
keywords: ADARs; Editome; RNA Editing; Transcriptome