Posted: November 2, 2017

View the TCGA study of sarcoma here

TCGA Soft Tissue Sarcoma Study Charts Diverse Landscape of Molecular Changes

The Cancer Genome Atlas (TCGA) Research Network uncovered a diverse array of molecular alterations underlying 206 cases of adult soft tissue sarcomas. There are more than 70 types of these rare diseases arising from different tissue types, but they can be broadly grouped by simple and complex karyotype. In this study, published online in Cell on November 2, researchers investigated six major types of sarcoma, including five with complex karyotypes: dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPMS), myxofibrosarcoma (MFS), and malignant peripheral nerve sheath tumor (MPNST) and one with a simple karyotype: synovial sarcoma (SS). The researchers found that a wide range of oncogenic drivers can occur and predict markers of outcome and identify potential therapeutic targets for various molecular subtypes.

A low mutation burden is a distinctive feature of rare cancers, and indeed researchers found few small-scale mutations in this collection of sarcomas. Only TP53, ATRX, and RB1 were recurrently mutated across the different types. The mutational signatures found in the sarcomas contained elements of prior described patterns, including those resulting from clock-like mutation processes. The complex karyotype sarcomas frequently had copy number alterations spanning various functional pathways, including the p53 and RB1 cell cycle pathways. The simple karyotype SS cases harbored SSX gene fusions and often an additional fusion in TERT or other gene. When considering genes related to immune response and inflammation, the researchers found the level of immune infiltration to differentially affect outcome in the different sarcoma types, indicating that immunotherapy agents may be applicable for certain types of the disease.

The researchers also analyzed the sarcomas types individually, though with the limitation of having few samples for many subtypes. They identified JUN amplification as a potential marker of poor survival and a putative therapeutic target in a subset of DDLPS sarcomas. Though the gynecologic and soft tissue types of LMS were found to be molecularly distinct, inhibitors of the PI3K-AKT-mTOR signaling pathway may be applicable to both groups. Finally, molecular analyses indicated that UPS and MFS are of the same cellular origin but with varying amounts of histologic myxoid (mucoid tissue) and some may be driven by alterations in the Hippo pathway.

The diverse array of mutations, altered pathways, and driving processes uncovered by the researchers demonstrate how soft tissue sarcomas, like many other cancers, encompass numerous distinct diseases that each require a deep molecular understanding. This study highlights the need for further studies on the various types of this disease in order to guide the development and application of therapies. TCGA is a collaboration jointly supported and managed by the National Cancer Institute and the National Human Genome Research Institute, both parts of the National Institutes of Health.