title: Paired Exome Analysis Reveals Clonal Evolution and Potential Therapeutic Targets in Urothelial Carcinoma.
abstract: Greater knowledge concerning tumor heterogeneity and clonality is needed to determine the impact of targeted treatment in the setting of bladder cancer. In this study, we performed whole-exome, transcriptome, and deep-focused sequencing of metachronous tumors from 29 patients initially diagnosed with early-stage bladder tumors (14 with nonprogressive disease and 15 with progressive disease). Tumors from patients with progressive disease showed a higher variance of the intrapatient mutational spectrum and a higher frequency of APOBEC-related mutations. Allele-specific expression was also higher in these patients, particularly in tumor suppressor genes. Phylogenetic analysis revealed a common origin of the metachronous tumors, with a higher proportion of clonal mutations in the ancestral branch; however, 19 potential therapeutic targets were identified as both ancestral and tumor-specific alterations. Few subclones were present based on PyClone analysis. Our results illuminate tumor evolution and identify candidate therapeutic targets in bladder cancer. Cancer Res; 76(19); 5894-906. ©2016 AACR.
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lamy
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Iver
authors.initials: I
authors.lastname: Nordentoft
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Karin
authors.initials: K
authors.lastname: Birkenkamp-Demtröder
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mathilde Borg Houlberg
authors.initials: MB
authors.lastname: Thomsen
authors.affiliation: Department of Bioinformatic Research, Aarhus University, Aarhus, Denmark.
authors.forename: Palle
authors.initials: P
authors.lastname: Villesen
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Vang
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hedegaard
authors.affiliation: Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.affiliation: Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jørgen Bjerggaard
authors.initials: JB
authors.lastname: Jensen
authors.affiliation: Department of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Høyer
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jakob Skou
authors.initials: JS
authors.lastname: Pedersen
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. lars@clin.au.dk.
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060965:Clonal Evolution; D003564:Cytidine Deaminase / Q000235:genetics; D059472:Exome; D006801:Humans; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000235:genetics; D009154:Mutation; D010802:Phylogeny; D011506:Proteins / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: D015778:Minor Histocompatibility Antigens; D011506:Proteins; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; C121399:APOBEC3A protein, human; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase