title: Frequent alterations and epigenetic silencing of differentiation pathway genes in structurally rearranged liposarcomas.
abstract: We explored diverse alterations contributing to liposarcomagenesis by sequencing the genome, exome, transcriptome, and cytosine methylome of a primary and recurrent dedifferentiated liposarcoma (DLPS) from distinct chemotherapy/radiotherapy-naïve patients. The liposarcoma genomes had complex structural rearrangements, but in different patterns, and with varied effects on the structure and expression of affected genes. While the point mutation rate was modest, integrative analyses and additional screening identified somatic mutations in HDAC1 in 8.3% of DLPS. Liposarcoma methylomes revealed alterations in differentiation pathway genes, including CEBPA methylation in 24% of DLPS. Treatment with demethylating agents, which restored CEBPA expression in DLPS cells, was anti-proliferative and pro-apoptotic in vitro and reduced tumor growth in vivo. Both genetic and epigenetic abnormalities established a role for small RNAs in liposarcomagenesis, typified by methylation-induced silencing of microRNA-193b in DLPS but not its well-differentiated counterpart. These findings reveal an unanticipated role for epigenetic abnormalities in DLPS tumors and suggest demethylating agents as potential therapeutics.
  
  
  CONCLUSIONS
  Multimodality sequence analysis of DLPS revealed recurrent mutations and epigenetic abnormalities critical to liposarcomagenesis and to the suppression of adipocyte differentiation. Pharmacologic inhibition of DNA methylation promoted apoptosis and differentiated DLPS cells in vitro and inhibited tumor growth in vivo, providing a rationale for investigating methylation inhibitors in this disease.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, NY 10065, USA. taylorb@cbio.mskcc.org
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Penelope L
authors.initials: PL
authors.lastname: DeCarolis
authors.forename: Christina V
authors.initials: CV
authors.lastname: Angeles
authors.forename: Fabienne
authors.initials: F
authors.lastname: Brenet
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Scandura
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Agnes J
authors.initials: AJ
authors.lastname: Viale
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015321:Gene Rearrangement; D020868:Gene Silencing; D056284:Histone Deacetylase 1 / Q000235:genetics; D006801:Humans; D008080:Liposarcoma / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D015398:Signal Transduction
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1