title: Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma.
abstract: Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are closely related tumors commonly characterized by MDM2/CDK4 gene amplification, and lack clinically effective treatment options when inoperable. To identify novel therapeutic targets, we performed targeted genomic sequencing analysis of 19 WDLPS and 37 DDLPS tumor samples using a panel of 104 cancer-related genes (NCC oncopanel v3) developed specifically for genomic testing to select suitable molecular targeted therapies. The results of this analysis indicated that these sarcomas had very few gene mutations and a high frequency of amplifications of not only MDM2 and CDK4 but also other genes. Potential driver mutations were found in only six (11%) samples; however, gene amplification events (other than MDM2 and CDK4 amplification) were identified in 30 (54%) samples. Receptor tyrosine kinase (RTK) genes in particular were amplified in 18 (32%) samples. In addition, growth of a WDLPS cell line with IGF1R amplification was suppressed by simultaneous inhibition of CDK4 and IGF1R, using palbociclib and NVP-AEW541, respectively. Combination therapy with CDK4 and RTK inhibitors may be an effective therapeutic option for WDLPS/DDLPS patients with RTK gene amplification.
authors.affiliation: Division of Rare Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.|Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Asano
authors.affiliation: Department of Pathology and Clinical Laboratory, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Department of Clinical Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Mitani
authors.affiliation: Department of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Kobayashi
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Bunsyo
authors.initials: B
authors.lastname: Shiotani
authors.affiliation: Department of Urology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Motokiyo
authors.initials: M
authors.lastname: Komiyama
authors.affiliation: Department of Urology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujimoto
authors.affiliation: Department of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Chuman
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Division of Translational Genomics, National Cancer Center-Exploratory Oncology Research and Clinical Trial Center, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Bioinformatics, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kato
authors.affiliation: Division of Translational Genomics, National Cancer Center-Exploratory Oncology Research and Clinical Trial Center, Chuo-ku, Tokyo 104-0045, Japan.|Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Department of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kawai
authors.affiliation: Division of Rare Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Clinical Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.|Division of Translational Genomics, National Cancer Center-Exploratory Oncology Research and Clinical Trial Center, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008080:Liposarcoma / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000235:genetics*
chemical_list: D020794:Receptor Protein-Tyrosine Kinases
keywords: dedifferentiated liposarcoma; liposarcoma; next-generation sequencing; receptor tyrosine kinase; well-differentiated liposarcoma