Genomic landscape of liposarcoma

Deepika Kanojia, Yasunobu Nagata, Manoj Garg, Dhong Hyun Lee, Aiko Sato, Kenichi Yoshida, Yusuke Sato, Masashi Sanada, Anand Mayakonda, Christoph Bartenhagen, Hans Ulrich Klein, Ngan B. Doan, Jonathan W. Said, S. Mohith, Swetha Gunasekar, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Ola MyklebostHenry Yang, Martin Dugas, Leonardo A. Meza-Zepeda, Allan W. Silberman, Charles Forscher, Jeffrey W. Tyner, Seishi Ogawa, H. Phillip Koeffler

Research output: Contribution to journalArticle

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)42429-42444
Number of pages16
JournalOncotarget
Volume6
Issue number40
DOIs
StatePublished - Jan 1 2015

Keywords

  • Exome sequencing
  • Intra-tumor heterogeneity
  • Liposarcoma
  • SNP array
  • Therapeutics

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Kanojia, D., Nagata, Y., Garg, M., Lee, D. H., Sato, A., Yoshida, K., Sato, Y., Sanada, M., Mayakonda, A., Bartenhagen, C., Klein, H. U., Doan, N. B., Said, J. W., Mohith, S., Gunasekar, S., Shiraishi, Y., Chiba, K., Tanaka, H., Miyano, S., ... Phillip Koeffler, H. (2015). Genomic landscape of liposarcoma. Oncotarget, 6(40), 42429-42444. https://doi.org/10.18632/oncotarget.6464