title: Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors.
abstract: Gastrointestinal stromal tumors represent the most common mesenchymal tumor of the digestive tract, driven by gain-of-function mutations in KIT. Despite its proven benefits, half of the patients treated with imatinib show disease progression within 2 years due to secondary resistance mutations in KIT. It remains unclear how the genomic and transcriptomic features change during the acquisition of imatinib resistance. Here, we performed exome sequencing and microarray transcription analysis for four imatinib-resistant cell lines and one cell line briefly exposed to imatinib. We also performed exome sequencing of clinical tumor samples. The cell line briefly exposed to imatinib exhibited few single-nucleotide variants and copy-number alterations, but showed marked upregulation of genes related to detoxification and downregulation of genes involved in cell cycle progression. Meanwhile, resistant cell lines harbored numerous genomic changes: amplified genes related to detoxification and deleted genes with cyclin-dependent kinase activity. Some variants in the resistant samples were traced back to the drug-sensitive samples, indicating the presence of ancestral subpopulations. The subpopulations carried variants associated with cell death. Pre-existing cancer cells with genetic alterations promoting apoptosis resistance may serve as a basis whereby cancer cells with critical mutations, such as secondary KIT mutations, can establish full imatinib resistance. © 2017 The Authors Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2 E2, Yamadaoka, Suita City, Osaka, 565-0871, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Bioinformatics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|JST, CREST, 5-3 Yonbancho, Chiyoda-ku, Tokyo, 102-0081, Japan.
authors.forename: Asmaa
authors.initials: A
authors.lastname: Elzawahry
authors.affiliation: Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Mimaki
authors.affiliation: Department of Bioinformatics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Eisaku
authors.initials: E
authors.lastname: Furukawa
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2 E2, Yamadaoka, Suita City, Osaka, 565-0871, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Nakatsuka
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2 E2, Yamadaoka, Suita City, Osaka, 565-0871, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nishigaki
authors.affiliation: Laboratory for Immune Signal, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki City, Osaka, 567-0085, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.affiliation: Laboratory for Immune Signal, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki City, Osaka, 567-0085, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
authors.affiliation: Department of Surgical Pathology, Hyogo Medical College, 1-1, Mukogawa-cho, Nishinomiya City, Hyogo, 663-8501, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tsuchihara
authors.affiliation: Department of Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Toshirou
authors.initials: T
authors.lastname: Nishida
authors.affiliation: Department of Bioinformatics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|JST, CREST, 5-3 Yonbancho, Chiyoda-ku, Tokyo, 102-0081, Japan.
authors.forename: Mamoru
authors.identifier: 0000-0002-8485-8316
authors.initials: M
authors.lastname: Kato
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D023281:Genomics / Q000379:methods*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit