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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Amidinotransferases / antagonists & inhibitors
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Amidinotransferases / genetics*
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Amidinotransferases / metabolism
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Base Sequence
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Carcinoma, Renal Cell / genetics*
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Carcinoma, Renal Cell / mortality
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Carcinoma, Renal Cell / pathology
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Cell Line
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Cohort Studies
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Female
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High-Throughput Nucleotide Sequencing
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Humans
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Kallikreins / antagonists & inhibitors
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Kallikreins / genetics*
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Kallikreins / metabolism
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Kidney Neoplasms / genetics*
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Kidney Neoplasms / mortality
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Kidney Neoplasms / pathology
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Male
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Middle Aged
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Molecular Sequence Data
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Oncogene Proteins, Fusion / antagonists & inhibitors
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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RNA Interference
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RNA, Messenger / chemistry
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Sequence Analysis, RNA
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Survival Analysis
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Up-Regulation
Substances
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Oncogene Proteins, Fusion
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RNA, Messenger
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RNA, Small Interfering
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Amidinotransferases
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glycine amidinotransferase
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Kallikreins
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kallikrein 4
Associated data
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GENBANK/KM576708
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