Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

The Cancer Genome Atlas Research Network

doi:10.1016/j.cell.2017.10.014

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

The Cancer Genome Atlas Research Network

Research output: Contribution to journal › Article › peer-review

620 Scopus citations

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 language	English (US)
Pages (from-to)	950-965.e28
Journal	Cell
Volume	171
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2017.10.014
State	Published - Nov 2 2017

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2017.10.014

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@article{9853cc98e0f4426db638967f31d9b56e,

title = "Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas",

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.",

keywords = "DNA methylation, The Cancer Genome Atlas, dedifferentiated liposarcoma, genomics, immune infiltration, leiomyosarcoma, molecular subtype, myxofibrosarcoma, pleomorphism, undifferentiated pleomorphic sarcoma",

author = "{The Cancer Genome Atlas Research Network} and Adam Abeshouse and Clement Adebamowo and Adebamowo, {Sally N.} and Rehan Akbani and Teniola Akeredolu and Adrian Ally and Anderson, {Matthew L.} and Pavana Anur and Appelbaum, {Elizabeth L.} and Joshua Armenia and Auman, {J. Todd} and Bailey, {Matthew H.} and Laurence Baker and Miruna Balasundaram and Saianand Balu and Barthel, {Floris P.} and John Bartlett and Baylin, {Stephen B.} and Madhusmita Behera and Dmitry Belyaev and Joesph Bennett and Christopher Benz and Rameen Beroukhim and Michael Birrer and Th{\`e}r{\'e}se Bocklage and Tom Bodenheimer and Lori Boice and Bootwalla, {Moiz S.} and Jay Bowen and Reanne Bowlby and Jeff Boyd and Brohl, {Andrew S.} and Denise Brooks and Lauren Byers and Rebecca Carlsen and Patricia Castro and Chen, {Hsiao Wei} and Cherniack, {Andrew D.} and Fr{\'e}deric Chibon and Lynda Chin and Juok Cho and Eric Chuah and Sudha Chudamani and Carrie Cibulskis and Cooper, {Lee A.D.} and Leslie Cope and Cordes, {Matthew G.} and Davis, {Lara E.} and Mills, {Gordon B.} and Paul Spellman",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = nov,

day = "2",

doi = "10.1016/j.cell.2017.10.014",

language = "English (US)",

volume = "171",

pages = "950--965.e28",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "4",

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T1 - Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

AU - The Cancer Genome Atlas Research Network

AU - Abeshouse, Adam

AU - Adebamowo, Clement

AU - Adebamowo, Sally N.

AU - Akbani, Rehan

AU - Akeredolu, Teniola

AU - Ally, Adrian

AU - Anderson, Matthew L.

AU - Anur, Pavana

AU - Appelbaum, Elizabeth L.

AU - Armenia, Joshua

AU - Auman, J. Todd

AU - Bailey, Matthew H.

AU - Baker, Laurence

AU - Balasundaram, Miruna

AU - Balu, Saianand

AU - Barthel, Floris P.

AU - Bartlett, John

AU - Baylin, Stephen B.

AU - Behera, Madhusmita

AU - Belyaev, Dmitry

AU - Bennett, Joesph

AU - Benz, Christopher

AU - Beroukhim, Rameen

AU - Birrer, Michael

AU - Bocklage, Thèrése

AU - Bodenheimer, Tom

AU - Boice, Lori

AU - Bootwalla, Moiz S.

AU - Bowen, Jay

AU - Bowlby, Reanne

AU - Boyd, Jeff

AU - Brohl, Andrew S.

AU - Brooks, Denise

AU - Byers, Lauren

AU - Carlsen, Rebecca

AU - Castro, Patricia

AU - Chen, Hsiao Wei

AU - Cherniack, Andrew D.

AU - Chibon, Fréderic

AU - Chin, Lynda

AU - Cho, Juok

AU - Chuah, Eric

AU - Chudamani, Sudha

AU - Cibulskis, Carrie

AU - Cooper, Lee A.D.

AU - Cope, Leslie

AU - Cordes, Matthew G.

AU - Davis, Lara E.

AU - Mills, Gordon B.

AU - Spellman, Paul

PY - 2017/11/2

Y1 - 2017/11/2

N2 - 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.

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.

KW - DNA methylation

KW - The Cancer Genome Atlas

KW - dedifferentiated liposarcoma

KW - genomics

KW - immune infiltration

KW - leiomyosarcoma

KW - molecular subtype

KW - myxofibrosarcoma

KW - pleomorphism

KW - undifferentiated pleomorphic sarcoma

UR - http://www.scopus.com/inward/record.url?scp=85032697928&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032697928&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.10.014

DO - 10.1016/j.cell.2017.10.014

M3 - Article

C2 - 29100075

AN - SCOPUS:85032697928

SN - 0092-8674

VL - 171

SP - 950-965.e28

JO - Cell

JF - Cell

IS - 4

ER -

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Abstract

Keywords

ASJC Scopus subject areas

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