Genomic landscape of liposarcoma

// Deepika Kanojia 1 , Yasunobu Nagata 2 , Manoj Garg 1 , Dhong Hyun Lee 3 , Aiko Sato 2 , Kenichi Yoshida 2 , Yusuke Sato 2 , Masashi Sanada 2,4 , Anand Mayakonda 1 , Christoph Bartenhagen 5 , Hans-Ulrich Klein 5 , Ngan B. Doan 6 , Jonathan W. Said 6 , S. Mohith 1 , Swetha Gunasekar 1 , Yuichi Shiraishi 7 , Kenichi Chiba 7 , Hiroko Tanaka 8 , Satoru Miyano 7,8 , Ola Myklebost 9,10 , Henry Yang 1 , Martin Dugas 5 , Leonardo A. Meza-Zepeda 9 , Allan W. Silberman 11 , Charles Forscher 3 , Jeffrey W. Tyner 12 , Seishi Ogawa 2,* and H. Phillip Koeffler 1,3,13,* 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore 2 Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 3 Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, School of Medicine, Los Angeles, California, USA 4 Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan 5 Institute of Medical Informatics, University of Munster, Munster, Germany 6 Department of Pathology and Laboratory Medicine, Santa Monica-University of California-Los Angeles Medical Center, Los Angeles, California, USA 7 Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 8 Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 9 Norwegian Cancer Genomics Consortium and Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway 10 Department of Molecular Bioscience, University of Oslo, Oslo, Norway 11 Department of Surgery, Cedars Sinai Medical Center, Division of Surgical Oncology, Los Angeles, California, USA 12 Knight Cancer Institute, Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA 13 National University Cancer Institute, National University Hospital, Singapore * These authors jointly directed this work Correspondence to: Deepika Kanojia, email: // Keywords : liposarcoma, exome sequencing, SNP array, intra-tumor heterogeneity, therapeutics Received : September 07, 2015 Accepted : November 26, 2015 Published : December 04, 2015 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.