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ADAR-Mediated RNA Editing Predicts Progression and Prognosis of Gastric Cancer. (Gastroenterology, Jun 2016)

Chan TH1, Qamra A2, Tan KT1, Guo J1, Yang H1, Qi L1, Lin JS1, Ng VH1, Song Y1, Hong H1, Tay ST3, Liu Y4, Lee J5, Rha SY6, Feng Z7, So JB7, Bin Tean T8, Guan YK9, Rozen S10, Tenen DG11, Tan P12, Chen L13

1Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
4Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore; Singapore-MIT Alliance, Singapore.
5Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, South Korea.
6Yongsei Cancer Center, 50 Yonsei-ro, Seodaemun-gu, Seoul, South Korea.
7Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
8Cancer Science Institute of Singapore, National University of Singapore, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore.
9Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Gastroenterology and Hepatology, National University Health System, Singapore.
10Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore; Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore.
11Cancer Science Institute of Singapore, National University of Singapore, Singapore; Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.
12Cancer Science Institute of Singapore, National University of Singapore, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore; Cellular and Molecular Research, National Cancer Centre, Singapore 169610, Singapore; Genome Institute of Singapore, 60 Biopolis Street, Genome 02-01, Singapore 138672, Singapore. Electronic address: gmstanp@duke-nus.edu.sg.
13Cancer 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.

Abstract:

BACKGROUD AND AIMS:

Gastric cancer (GC) is the third leading cause of global cancer mortality. Adenosine-to-Inosine (A-to-I) RNA editing is a recently-described novel epigenetic mechanism involving sequence alterations at the RNA but not DNA level, primarily mediated by ADAR enzymes (Adenosine DeAminase that act on RNA). Emerging evidence suggests a role for RNA editing and ADARs in cancer, however the relation between RNA editing and GC development and progression remains unknown.

METHODS:

In this study, we leveraged on the next-generation sequencing (NGS) transcriptomics to demarcate the GC RNA editing landscape and the role of ADARs in this deadly malignancy.

RESULTS:

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→Arg) confers a loss-of-function phenotype that neutralizes the tumorigenic ability of the unedited PODXL.

CONCLUSIONS:

Our study highlights a major role for RNA editing in GC disease and progression, an observation potentially missed by previous NGS 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.

KEYWORDS: ADARs; RNA editing; Transcriptome; editome

 

View the summary video here.

PMID: 27373511