title: Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors.
abstract: Identification of driver genes contributes to the understanding of cancer etiology and is imperative for the development of individualized therapies. Gene amplification is a major event in oncogenesis. Driver genes with tumor-specific amplification-dependent overexpression can be therapeutic targets. In this study, we aimed to identify amplification-dependent driver genes in 1,454 solid tumors, across more than 15 cancer types, by integrative analysis of gene expression and copy number. Amplification-dependent overexpression of 64 known driver oncogenes were found in 587 tumors (40%); genes frequently observed were MYC (25%) and MET (18%) in colorectal cancer; SKP2 (21%) in lung squamous cell carcinoma; HIST1H3B (19%) and MYCN (13%) in liver cancer; KIT (57%) in gastrointestinal stromal tumors; and FOXL2 (12%) in squamous cell carcinoma across tissues. Genomic aberrations in 138 known cancer driver genes and 491 established fusion genes were found in 1,127 tumors (78%). Further analyses of 820 cancer-related genes revealed 16 as potential driver genes, with amplification-dependent overexpression restricted to the remaining 22% of samples (327 tumors) initially undetermined genetic drivers. Among them, AXL, which encodes a receptor tyrosine kinase, was recurrently overexpressed and amplified in sarcomas. Our studies of amplification-dependent overexpression identified potential drug targets in individual tumors.
authors.affiliation: Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan. k.ohshima@scchr.jp.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ohshima
authors.affiliation: Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hatakeyama
authors.affiliation: Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.|SRL, Inc., Tokyo, 163-0409, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagashima
authors.affiliation: Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kanto
authors.affiliation: Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Doi
authors.affiliation: Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.affiliation: Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.|SRL, Inc., Tokyo, 163-0409, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shimoda
authors.affiliation: Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.|SRL, Inc., Tokyo, 163-0409, Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Tanabe
authors.affiliation: Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Ohnami
authors.affiliation: Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ohnami
authors.affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Masakuni
authors.initials: M
authors.lastname: Serizawa
authors.affiliation: Experimental Animal Facility, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Urakami
authors.affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.|Region Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kusuhara
authors.affiliation: Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Mochizuki
authors.affiliation: Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, 411-8777, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D009857:Oncogenes