TY - JOUR
T1 - Genomic landscape of liposarcoma
AU - Kanojia, Deepika
AU - Nagata, Yasunobu
AU - Garg, Manoj
AU - Lee, Dhong Hyun
AU - Sato, Aiko
AU - Yoshida, Kenichi
AU - Sato, Yusuke
AU - Sanada, Masashi
AU - Mayakonda, Anand
AU - Bartenhagen, Christoph
AU - Klein, Hans Ulrich
AU - Doan, Ngan B.
AU - Said, Jonathan W.
AU - Mohith, S.
AU - Gunasekar, Swetha
AU - Shiraishi, Yuichi
AU - Chiba, Kenichi
AU - Tanaka, Hiroko
AU - Miyano, Satoru
AU - Myklebost, Ola
AU - Yang, Henry
AU - Dugas, Martin
AU - Meza-Zepeda, Leonardo A.
AU - Silberman, Allan W.
AU - Forscher, Charles
AU - Tyner, Jeffrey W.
AU - Ogawa, Seishi
AU - Phillip Koeffler, H.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Exome sequencing
KW - Intra-tumor heterogeneity
KW - Liposarcoma
KW - SNP array
KW - Therapeutics
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U2 - 10.18632/oncotarget.6464
DO - 10.18632/oncotarget.6464
M3 - Article
C2 - 26643872
AN - SCOPUS:84952333753
SN - 1949-2553
VL - 6
SP - 42429
EP - 42444
JO - Oncotarget
JF - Oncotarget
IS - 40
ER -