title: Functional characterization of BC039389-GATM and KLK4-KRSP1 chimeric read-through transcripts which are up-regulated in renal cell cancer.
abstract: BACKGROUND
  Chimeric read-through RNAs are transcripts originating from two directly adjacent genes (<10 kb) on the same DNA strand. Although they are found in next-generation whole transcriptome sequencing (RNA-Seq) data on a regular basis, investigating them further has usually been refrained from. Therefore, their expression patterns or functions in general, and in oncogenesis in particular, are poorly understood.
  
  
  RESULTS
  We used paired-end RNA-Seq and a specifically designed computational data analysis pipeline (FusionSeq) to nominate read-through events in a small discovery set of renal cell carcinomas (RCC) and confirmed them in a larger validation cohort. 324 read-through events were called overall; 22/27 (81%) selected nominees passed validation with conventional PCR and were sequenced at the junction region. We frequently identified various isoforms of a given read-through event. 2/22 read-throughs were up-regulated: BC039389-GATM was higher expressed in RCC compared to benign adjacent kidney; KLK4-KRSP1 was expressed in 46/169 (27%) RCCs, but rarely in normal tissue. KLK4-KRSP1 expression was associated with worse clinical outcome in the patient cohort. In cell lines, both read-throughs influenced molecular mechanisms (i.e. target gene expression or migration/invasion) in a way that counteracted the effect of the respective parent transcript GATM or KLK4.
  
  
  CONCLUSIONS
  Our data suggests that the up-regulation of read-through RNA chimeras in tumors is not random but causes regulatory effects on cellular mechanisms and may impact patient survival.
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. dorothee.pflueger@usz.ch.|Competence Center Personalized Medicine, ETH and University of Zurich, Zurich, Switzerland. dorothee.pflueger@usz.ch.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Pflueger
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. christiane.mittmann@usz.ch.
authors.forename: Christiane
authors.initials: C
authors.lastname: Mittmann
authors.affiliation: Cancer Registry Zurich and Zug, University Hospital Zurich, Zurich, Switzerland. silvia.dehler@usz.ch.
authors.forename: Silvia
authors.initials: S
authors.lastname: Dehler
authors.affiliation: Institute of Precision Medicine of Weill Cornell Medical College and New York-Presbyterian Hospital, New York, USA. rubinma@med.cornell.edu.|Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, USA. rubinma@med.cornell.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. holger.moch@usz.ch.|Competence Center Personalized Medicine, ETH and University of Zurich, Zurich, Switzerland. holger.moch@usz.ch.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. peter.schraml@usz.ch.
authors.forename: Peter
authors.initials: P
authors.lastname: Schraml
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000579:Amidinotransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002460:Cell Line; D015331:Cohort Studies; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017423:Sequence Analysis, RNA; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000579:Amidinotransferases; C020681:glycine amidinotransferase; D007610:Kallikreins; C120801:kallikrein 4