title: Genomic landscape of liposarcoma.
abstract: Liposarcoma (LPS) is the most common type of soft tissue sarcoma accounting for 20% of all adult sarcomas. Due to absence of clinically effective treatment options in inoperable situations and resistance to chemotherapeutics, a critical need exists to identify novel therapeutic targets. We analyzed LPS genomic landscape using SNP arrays, whole exome sequencing and targeted exome sequencing to uncover the genomic information for development of specific anti-cancer targets. SNP array analysis indicated known amplified genes (MDM2, CDK4, HMGA2) and important novel genes (UAP1, MIR557, LAMA4, CPM, IGF2, ERBB3, IGF1R). Carboxypeptidase M (CPM), recurrently amplified gene in well-differentiated/de-differentiated LPS was noted as a putative oncogene involved in the EGFR pathway. Notable deletions were found at chromosome 1p (RUNX3, ARID1A), chromosome 11q (ATM, CHEK1) and chromosome 13q14.2 (MIR15A, MIR16-1). Significantly and recurrently mutated genes (false discovery rate < 0.05) included PLEC (27%), MXRA5 (21%), FAT3 (24%), NF1 (20%), MDC1 (10%), TP53 (7%) and CHEK2 (6%). Further, in vitro and in vivo functional studies provided evidence for the tumor suppressor role for Neurofibromin 1 (NF1) gene in different subtypes of LPS. Pathway analysis of recurrent mutations demonstrated signaling through MAPK, JAK-STAT, Wnt, ErbB, axon guidance, apoptosis, DNA damage repair and cell cycle pathways were involved in liposarcomagenesis. Interestingly, we also found mutational and copy number heterogeneity within a primary LPS tumor signifying the importance of multi-region sequencing for cancer-genome guided therapy. In summary, these findings provide insight into the genomic complexity of LPS and highlight potential druggable pathways for targeted therapeutic approach.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Deepika
authors.initials: D
authors.lastname: Kanojia
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Manoj
authors.initials: M
authors.lastname: Garg
authors.affiliation: Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, School of Medicine, Los Angeles, California, USA.
authors.forename: Dhong Hyun
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Anand
authors.initials: A
authors.lastname: Mayakonda
authors.affiliation: Institute of Medical Informatics, University of Münster, Münster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bartenhagen
authors.affiliation: Institute of Medical Informatics, University of Münster, Münster, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Klein
authors.affiliation: Department of Pathology and Laboratory Medicine, Santa Monica-University of California-Los Angeles Medical Center, Los Angeles, California, USA.
authors.forename: Ngan B
authors.initials: NB
authors.lastname: Doan
authors.affiliation: Department of Pathology and Laboratory Medicine, Santa Monica-University of California-Los Angeles Medical Center, Los Angeles, California, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Said
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Mohith
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Swetha
authors.initials: S
authors.lastname: Gunasekar
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Norwegian Cancer Genomics Consortium and Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.|Department of Molecular Bioscience, University of Oslo, Oslo, Norway.
authors.forename: Ola
authors.initials: O
authors.lastname: Myklebost
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Institute of Medical Informatics, University of Münster, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.affiliation: Norwegian Cancer Genomics Consortium and Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Meza-Zepeda
authors.affiliation: Department of Surgery, Cedars Sinai Medical Center, Division of Surgical Oncology, Los Angeles, California, USA.
authors.forename: Allan W
authors.initials: AW
authors.lastname: Silberman
authors.affiliation: Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, School of Medicine, Los Angeles, California, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Forscher
authors.affiliation: Knight Cancer Institute, Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, School of Medicine, Los Angeles, California, USA.|National University Cancer Institute, National University Hospital, Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000818:Animals; D004252:DNA Mutational Analysis; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D064593:Heterografts; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008080:Liposarcoma / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012983:Soft Tissue Neoplasms / Q000235:genetics*; D059467:Transcriptome
keywords: SNP array; exome sequencing; intra-tumor heterogeneity; liposarcoma; therapeutics