title: High frequency of fusion transcripts involving TCF7L2 in colorectal cancer: novel fusion partner and splice variants.
abstract: VTI1A-TCF7L2 was reported as a recurrent fusion gene in colorectal cancer (CRC), found to be expressed in three out of 97 primary cancers, and one cell line, NCI-H508, where a genomic deletion joins the two genes [1]. To investigate this fusion further, we analyzed high-throughput DNA and RNA sequencing data from seven CRC cell lines, and identified the gene RP11-57H14.3 (ENSG00000225292) as a novel fusion partner for TCF7L2. The fusion was discovered from both genome and transcriptome data in the HCT116 cell line. By triplicate nested RT-PCR, we tested both the novel fusion transcript and VTI1A-TCF7L2 for expression in a series of 106 CRC tissues, 21 CRC cell lines, 14 normal colonic mucosa, and 20 normal tissues from miscellaneous anatomical sites. Altogether, 42% and 45% of the CRC samples expressed VTI1A-TCF7L2 and TCF7L2-RP11-57H14.3 fusion transcripts, respectively. The fusion transcripts were both seen in 29% of the normal colonic mucosa samples, and in 25% and 75% of the tested normal tissues from other organs, revealing that the TCF7L2 fusion transcripts are neither specific to cancer nor to the colon and rectum. Seven different splice variants were detected for the VTI1A-TCF7L2 fusion, of which three are novel. Four different splice variants were detected for the TCF7L2-RP11-57H14.3 fusion. In conclusion, we have identified novel variants of VTI1A-TCF7L2 fusion transcripts, including a novel fusion partner gene, RP11-57H14.3, and demonstrated detectable levels in a large fraction of CRC samples, as well as in normal colonic mucosa and other tissue types. We suggest that the fusion transcripts observed in a high frequency of samples are transcription induced chimeras that are expressed at low levels in most samples. The similar fusion transcripts induced by genomic rearrangements observed in individual cancer cell lines may yet have oncogenic potential as suggested in the original study by Bass et al.
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital - Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Torfinn
authors.initials: T
authors.lastname: Nome
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital - Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Hoff
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital - Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne Cathrine
authors.initials: AC
authors.lastname: Bakken
authors.affiliation: University of Oslo, Oslo, Norway; Department of forensic pathology and clinical forensic medicine, Division for forensic medicine, The Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Torleiv O
authors.initials: TO
authors.lastname: Rognum
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital-Aker, Oslo, Norway.
authors.forename: Arild
authors.initials: A
authors.lastname: Nesbakken
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital - Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Rolf I
authors.initials: RI
authors.lastname: Skotheim
mesh_terms: D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000235:genetics*; D005091:Exons / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics; D056426:Genetic Loci; D015894:Genome, Human / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D015514:Oncogene Proteins, Fusion; D022821:RNA Splice Sites; D012333:RNA, Messenger; D058118:Transcription Factor 7-Like 2 Protein