Kanojia D1, Nagata Y2, Garg M1, Lee DH3, Sato A2, Yoshida K2, Sato Y2, Sanada M2,4, Mayakonda A1, Bartenhagen C5, Klein HU5, Doan NB6, Said JW6, Mohith S1, Gunasekar S1, Shiraishi Y7, Chiba K7, Tanaka H8, Miyano S7,8, Myklebost O9,10, Yang H1, Dugas M5, Meza-Zepeda LA9, Silberman AW11, Forscher C3, Tyner JW12, Ogawa S2, Koeffler HP1,3,13
1Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
3Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, School of Medicine, Los Angeles, California, USA.
4Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
5Institute of Medical Informatics, University of Münster, Münster, Germany.
6Department of Pathology and Laboratory Medicine, Santa Monica-University of California-Los Angeles Medical Center, Los Angeles, California, USA.
7Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
8Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
9Norwegian Cancer Genomics Consortium and Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
10Department of Molecular Bioscience, University of Oslo, Oslo, Norway.
11Department of Surgery, Cedars Sinai Medical Center, Division of Surgical Oncology, Los Angeles, California, USA.
12Knight Cancer Institute, Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA.
13National University Cancer Institute, National University Hospital, Singapore.
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.