Comprehensive and integrated genomic characterization of adult soft tissue sarcomas

AJ Lazar, MD McLellan, MH Bailey, CA Miller… - Cell, 2017 - discovery.ucl.ac.uk
AJ Lazar, MD McLellan, MH Bailey, CA Miller, EL Appelbaum, MG Cordes, CC Fronick…
Cell, 2017discovery.ucl.ac.uk
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 …
Summary
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.
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