Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types. Genetic analysis of soft tissue sarcomas shows that they are characterized predominantly by copy-number changes and offers insights into the immune microenviroment to inform clinical trials of checkpoint inhibitors.

Original languageEnglish (US)
Pages (from-to)950-965.e28
JournalCell
Volume171
Issue number4
DOIs
StatePublished - Nov 2 2017
Externally publishedYes

Fingerprint

Sarcoma
Tissue
Methylation
Refining
Genes
RNA
Messenger RNA
Proteins
Clinical Trials
Synovial Sarcoma
Neoplasms
p53 Genes
DNA Methylation

Keywords

  • dedifferentiated liposarcoma
  • DNA methylation
  • genomics
  • immune infiltration
  • leiomyosarcoma
  • molecular subtype
  • myxofibrosarcoma
  • pleomorphism
  • The Cancer Genome Atlas
  • undifferentiated pleomorphic sarcoma

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas. / The Cancer Genome Atlas Research Network.

In: Cell, Vol. 171, No. 4, 02.11.2017, p. 950-965.e28.

Research output: Contribution to journalArticle

The Cancer Genome Atlas Research Network 2017, 'Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas', Cell, vol. 171, no. 4, pp. 950-965.e28. https://doi.org/10.1016/j.cell.2017.10.014
The Cancer Genome Atlas Research Network. / Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas. In: Cell. 2017 ; Vol. 171, No. 4. pp. 950-965.e28.
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abstract = "Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types. Genetic analysis of soft tissue sarcomas shows that they are characterized predominantly by copy-number changes and offers insights into the immune microenviroment to inform clinical trials of checkpoint inhibitors.",
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AU - Boyd, Jeff

AU - Brohl, Andrew S.

AU - Brooks, Denise

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AU - Carlsen, Rebecca

AU - Castro, Patricia

AU - Chen, Hsiao Wei

AU - Cherniack, Andrew D.

AU - Chibon, Fréderic

AU - Chin, Lynda

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AU - Chuah, Eric

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AB - Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types. Genetic analysis of soft tissue sarcomas shows that they are characterized predominantly by copy-number changes and offers insights into the immune microenviroment to inform clinical trials of checkpoint inhibitors.

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KW - DNA methylation

KW - genomics

KW - immune infiltration

KW - leiomyosarcoma

KW - molecular subtype

KW - myxofibrosarcoma

KW - pleomorphism

KW - The Cancer Genome Atlas

KW - undifferentiated pleomorphic sarcoma

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