title: The genomic landscape of epithelioid sarcoma cell lines and tumours.
abstract: We carried out whole genome and transcriptome sequencing on four tumour/normal pairs of epithelioid sarcoma. These index cases were supplemented with whole transcriptome sequencing of three additional tumours and three cell lines. Unlike rhabdoid tumour (the other major group of SMARCB1-negative cancers), epithelioid sarcoma shows a complex genome with a higher mutational rate, comparable to that of ovarian carcinoma. Despite this mutational burden, SMARCB1 mutations remain the most frequently recurring event and are probably critical drivers of tumour formation. Several cases show heterozygous SMARCB1 mutations without inactivation of the second allele, and we explore this further in vitro. Finding CDKN2A deletions in our discovery cohort, we evaluated CDKN2A protein expression in a tissue microarray. Six out of 16 cases had lost CDKN2A in greater than or equal to 90% of cells, while the remaining cases had retained the protein. Expression analysis of epithelioid sarcoma cell lines by transcriptome sequencing shows a unique profile that does not cluster with any particular tissue type or with other SWI/SNF-aberrant lines. Evaluation of the levels of members of the SWI/SNF complex other than SMARCB1 revealed that these proteins are expressed as part of a residual complex, similarly to previously studied rhabdoid tumour lines. This residual SWI/SNF is susceptible to synthetic lethality and may therefore indicate a therapeutic opportunity.
authors.affiliation: Genetic Pathology Evaluation Centre, Vancouver, BC, Canada.
authors.forename: Farzad
authors.initials: F
authors.lastname: Jamshidi
authors.affiliation: BC Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Bashashati
authors.affiliation: BC Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Karey
authors.initials: K
authors.lastname: Shumansky
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Brendan
authors.initials: B
authors.lastname: Dickson
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Nalan
authors.initials: N
authors.lastname: Gokgoz
authors.affiliation: Division of Orthopaedic Surgery, University of Toronto, ON, Canada.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Wunder
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.|Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: BC Cancer Research Centre, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.|Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.affiliation: Genetic Pathology Evaluation Centre, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.affiliation: Genetic Pathology Evaluation Centre, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D055785:Gene Knockdown Techniques; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D060885:Multiplex Polymerase Chain Reaction; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D000071796:SMARCB1 Protein; D012509:Sarcoma / Q000235:genetics*; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome; D014162:Transfection
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors
keywords: SMARCB1; epithelioid sarcoma; genomic landscape; next-generation sequencing