title: Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.
abstract: Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.
authors.affiliation: Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jordi
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authors.lastname: Barretina
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Shantanu
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authors.lastname: Decarolis
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authors.lastname: Antipin
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authors.lastname: Beroukhim
authors.forename: John E
authors.initials: JE
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authors.forename: Charles
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authors.lastname: Hatton
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authors.initials: R
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authors.forename: Megan
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authors.lastname: Hanna
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authors.lastname: Sharpe
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authors.initials: TJ
authors.lastname: Fennell
authors.forename: Kristian
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authors.lastname: Cibulskis
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authors.lastname: Onofrio
authors.forename: Tsuyoshi
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authors.lastname: Saito
authors.forename: Neerav
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authors.lastname: Shukla
authors.forename: Christopher
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authors.lastname: Lau
authors.forename: Sven
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authors.lastname: Nelander
authors.forename: Serena J
authors.initials: SJ
authors.lastname: Silver
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.forename: Agnes
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authors.lastname: Viale
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authors.lastname: Winckler
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Alex
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authors.lastname: Lash
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Harold E
authors.initials: HE
authors.lastname: Varmus
authors.forename: Marc
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authors.lastname: Ladanyi
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Matthew
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authors.lastname: Meyerson
authors.forename: Samuel
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authors.lastname: Singer
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D016147:Genes, Tumor Suppressor; D016678:Genome; D051677:Histiocytoma, Malignant Fibrous / Q000235:genetics*; D006801:Humans; D008080:Liposarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology