title: Activation of an endogenous retrovirus-associated long non-coding RNA in human adenocarcinoma.
abstract: BACKGROUND
  Long non-coding RNAs (lncRNAs) are emerging as molecules that significantly impact many cellular processes and have been associated with almost every human cancer. Compared to protein-coding genes, lncRNA genes are often associated with transposable elements, particularly with endogenous retroviral elements (ERVs). ERVs can have potentially deleterious effects on genome structure and function, so these elements are typically silenced in normal somatic tissues, albeit with varying efficiency. The aberrant regulation of ERVs associated with lncRNAs (ERV-lncRNAs), coupled with the diverse range of lncRNA functions, creates significant potential for ERV-lncRNAs to impact cancer biology.
  
  
  METHODS
  We used RNA-seq analysis to identify and profile the expression of a novel lncRNA in six large cohorts, including over 7,500 samples from The Cancer Genome Atlas (TCGA).
  
  
  RESULTS
  We identified the tumor-specific expression of a novel lncRNA that we have named Endogenous retroViral-associated ADenocarcinoma RNA or 'EVADR', by analyzing RNA-seq data derived from colorectal tumors and matched normal control tissues. Subsequent analysis of TCGA RNA-seq data revealed the striking association of EVADR with adenocarcinomas, which are tumors of glandular origin. Moderate to high levels of EVADR were detected in 25 to 53% of colon, rectal, lung, pancreas and stomach adenocarcinomas (mean = 30 to 144 FPKM), and EVADR expression correlated with decreased patient survival (Cox regression; hazard ratio = 1.47, 95% confidence interval = 1.06 to 2.04, P = 0.02). In tumor sites of non-glandular origin, EVADR expression was detectable at only very low levels and in less than 10% of patients. For EVADR, a MER48 ERV element provides an active promoter to drive its transcription. Genome-wide, MER48 insertions are associated with nine lncRNAs, but none of the MER48-associated lncRNAs other than EVADR were consistently expressed in adenocarcinomas, demonstrating the specific activation of EVADR. The sequence and structure of the EVADR locus is highly conserved among Old World monkeys and apes but not New World monkeys or prosimians, where the MER48 insertion is absent. Conservation of the EVADR locus suggests a functional role for this novel lncRNA in humans and our closest primate relatives.
  
  
  CONCLUSIONS
  Our results describe the specific activation of a highly conserved ERV-lncRNA in numerous cancers of glandular origin, a finding with diagnostic, prognostic and therapeutic implications.
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Ave, Vancouver, British Columbia V5Z 1L3 Canada ; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z4 Canada.
authors.forename: Ewan A
authors.initials: EA
authors.lastname: Gibb
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Ave, Vancouver, British Columbia V5Z 1L3 Canada.
authors.forename: René L
authors.initials: RL
authors.lastname: Warren
authors.affiliation: Informatics and Biocomputing Platform, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3 Canada ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8 Canada.
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Wilson
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Ave, Vancouver, British Columbia V5Z 1L3 Canada ; Genome Science and Technology Program, University of British Columbia, Vancouver, British Columbia V6T 1Z4 Canada.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Brown
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Ave, Vancouver, British Columbia V5Z 1L3 Canada.
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Robertson
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Ave, Vancouver, British Columbia V5Z 1L3 Canada ; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z4 Canada ; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6 Canada.
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Morin
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Ave, Vancouver, British Columbia V5Z 1L3 Canada ; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z4 Canada ; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6 Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Holt
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