title: Genomic spectra of biliary tract cancer.
abstract: The incidence of biliary tract cancer (BTC), including intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gallbladder cancer, has increased globally; however, no effective targeted molecular therapies have been approved at the present time. Here we molecularly characterized 260 BTCs and uncovered spectra of genomic alterations that included new potential therapeutic targets. Gradient spectra of mutational signatures with a higher burden of the APOBEC-associated mutation signature were observed in gallbladder cancer and ECC. Thirty-two significantly altered genes, including ELF3, were identified, and nearly 40% of cases harbored targetable genetic alterations. Gene fusions involving FGFR2 and PRKACA or PRKACB preferentially occurred in ICC and ECC, respectively, and the subtype-associated prevalence of actionable growth factor-mediated signals was noteworthy. The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules. Accordingly, immune-modulating therapies might also be potentially promising options for these patients.
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Totoki
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.|First Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Shirota
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Asmaa
authors.initials: A
authors.lastname: Elzawahry
authors.affiliation: Department of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kato
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hama
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Hosoda
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Urushidate
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Ohashi
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hiraoka
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.|Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ojima
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Kosuge
authors.affiliation: First Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyagawa
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.|Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
mesh_terms: D001661:Biliary Tract Neoplasms / Q000235:genetics*; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D017354:Point Mutation; D011379:Prognosis; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C105529:ELF3 protein, human; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human