title: High-resolution genomic mapping reveals consistent amplification of the fibroblast growth factor receptor substrate 2 gene in well-differentiated and dedifferentiated liposarcoma.
abstract: Well-differentiated liposarcoma (WDLS) is one of the most common malignant mesenchymal tumors and dedifferentiated liposarcoma (DDLS) is a malignant tumor consisting of both WDLS and a transformed nonlipogenic sarcomatous component. Cytogenetically, WDLS is characterized by the presence of ring or giant rod chromosomes containing several amplified genes, including MDM2, TSPAN31, CDK4, and others mainly derived from chromosome bands 12q13-15. However, the 12q13-15 amplicon is large and discontinuous. The focus of this study was to identify novel critical genes that are consistently amplified in primary (nonrecurrent) WDLS and with potential relevance for future targeted therapy. Using a high-resolution (5.0 kb) "single nucleotide polymorphism"/copy number variation microarray to screen the whole genome in a series of primary WDLS, two consistently amplified areas were found on chromosome 12: one region containing the MDM2 and CPM genes, and another region containing the FRS2 gene. Based on these findings, we further validated FRS2 amplification in both WDLS and DDLS. Fluorescence in situ hybridization confirmed FRS2 amplification in all WDLS and DDLS tested (n = 57). Real time PCR showed FRS2 mRNA transcriptional upregulation in WDLS (n = 19) and DDLS (n = 13) but not in lipoma (n = 5) and normal fat (n = 9). Immunoblotting revealed high expression levels of phospho-FRS2 at Y436 and slightly overexpression of total FRS2 protein in liposarcoma but not in normal fat or preadipocytes. Considering the critical role of FRS2 in mediating fibroblast growth factor receptor signaling, our findings indicate that FRS2 signaling should be further investigated as a potential therapeutic target for liposarcoma.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Wang
authors.forename: Yan W
authors.initials: YW
authors.lastname: Asmann
authors.forename: Michele R
authors.initials: MR
authors.lastname: Erickson-Johnson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Oliveira
authors.forename: Hongying
authors.initials: H
authors.lastname: Zhang
authors.forename: Rafael D
authors.initials: RD
authors.lastname: Moura
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
authors.forename: Katelynn
authors.initials: K
authors.lastname: Bill
authors.forename: Ricardo V
authors.initials: RV
authors.lastname: Lloyd
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Yaszemski
authors.forename: Avudaiappan
authors.initials: A
authors.lastname: Maran
authors.forename: Andre M
authors.initials: AM
authors.lastname: Oliveira
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D056915:DNA Copy Number Variations; D058851:GPI-Linked Proteins / Q000235:genetics; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008080:Liposarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012189:Retrospective Studies; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C106534:FRS2 protein, human; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D017468:Receptors, Fibroblast Growth Factor; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C058479:carboxypeptidase M; D008666:Metalloendopeptidases