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Title: Genomic landscape of liposarcoma
Authors: 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
Myklebost, O
Yang, H 
Dugas, M
Meza-Zepeda, L.A
Silberman, A.W
Forscher, C
Tyner, J.W
Ogawa, S
Phillip Koeffler, H 
Keywords: ATM protein
carboxypeptidase M
checkpoint kinase 1
checkpoint kinase 2
cyclin dependent kinase 4
epidermal growth factor receptor
epidermal growth factor receptor 3
genomic DNA
high mobility group A2 protein
Janus kinase
laminin alpha4
microRNA 15a
microRNA 16
mitogen activated protein kinase
protein MDM2
protein p53
somatomedin B
somatomedin C receptor
STAT protein
transcription factor RUNX3
unclassified drug
Wnt protein
ARID1A gene
ATM gene
cancer genetics
CDK4 gene
CHEK1 gene
CHEK2 gene
chromosome 11q
chromosome 13q
chromosome 1p
controlled study
copy number variation
CPM gene
DNA damage
drug research
ERBB3 gene
FAT3 gene
gene amplification
gene deletion
gene mutation
genetic heterogeneity
genetic procedures
genome analysis
HMGA2 gene
human cell
human tissue
IGF1R gene
IGF2 gene
in vitro study
in vivo study
LAMA4 gene
major clinical study
MDC1 gene
MDM2 gene
MIR15A gene
MIR16 1 gene
MIR557 gene
molecularly targeted therapy
MXRA5 gene
NF1 gene
PLEC gene
polymerase chain reaction
RUNX3 gene
signal transduction
single nucleotide polymorphism
somatic mutation
targeted exome sequencing
TP53 gene
tumor differentiation
UAP1 gene
whole exome sequencing
DNA microarray
dna mutational analysis
flow cytometry
gene silencing
high throughput sequencing
nonobese diabetic mouse
SCID mouse
soft tissue tumor
DNA Mutational Analysis
Flow Cytometry
Gene Knockdown Techniques
High-Throughput Nucleotide Sequencing
Mice, Inbred NOD
Mice, SCID
Oligonucleotide Array Sequence Analysis
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Soft Tissue Neoplasms
Issue Date: 2015
Publisher: Impact Journals LLC
Citation: 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, Myklebost, O, Yang, H, Dugas, M, Meza-Zepeda, L.A, Silberman, A.W, Forscher, C, Tyner, J.W, Ogawa, S, Phillip Koeffler, H (2015). Genomic landscape of liposarcoma. Oncotarget 6 (40) : 42429-42444. ScholarBank@NUS Repository.
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.
Source Title: Oncotarget
ISSN: 19492553
DOI: 10.18632/oncotarget.6464
Appears in Collections:Staff Publications

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