title: Novel kinase fusion transcripts found in endometrial cancer.
abstract: Recent advances in RNA-sequencing technology have enabled the discovery of gene fusion transcripts in the transcriptome of cancer cells. However, it remains difficult to differentiate the therapeutically targetable fusions from passenger events. We have analyzed RNA-sequencing data and DNA copy number data from 25 endometrial cancer cell lines to identify potential therapeutically targetable fusion transcripts, and have identified 124 high-confidence fusion transcripts, of which 69% are associated with gene amplifications. As targetable fusion candidates, we focused on three in-frame kinase fusion transcripts that retain a kinase domain (CPQ-PRKDC, CAPZA2-MET, and VGLL4-PRKG1). We detected only CPQ-PRKDC fusion transcript in three of 122 primary endometrial cancer tissues. Cell proliferation of the fusion-positive cell line was inhibited by knocking down the expression of wild-type PRKDC but not by blocking the CPQ-PRKDC fusion transcript expression. Quantitative real-time RT-PCR demonstrated that the expression of the CPQ-PRKDC fusion transcript was significantly lower than that of wild-type PRKDC, corresponding to a low transcript allele fraction of this fusion, based on RNA-sequencing read counts. In endometrial cancers, the CPQ-PRKDC fusion transcript may be a passenger aberration related to gene amplification. Our findings suggest that transcript allele fraction is a useful predictor to find bona-fide therapeutic-targetable fusion transcripts.
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Tamura
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yoshihara
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamawaki
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Suda
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ishiguro
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Sosuke
authors.initials: S
authors.lastname: Adachi
authors.affiliation: Department of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Shujiro
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Division of Human Genetics, National Institute of Genetics, Mishima, Japan.
authors.forename: Ituro
authors.initials: I
authors.lastname: Inoue
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Genome Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Roel G W
authors.initials: RG
authors.lastname: Verhaak
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Enomoto
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011494:Protein Kinases