Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Abstract

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.

Undifferentiated Sarcomas Develop through Distinct Evolutionary Pathways

“…with at least one WGD, and for which our ploidy estimates matched the ploidy estimates in the TCGA publication (TCGA, 2017) (Figure S7B). Timing of WGD events further allowed for testing the possibility of an artefactual origin of the mutLo-rearrLo molecular class.…”

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

“…These images have generally been used solely to ensure the correct diagnosis, and panels of expert pathologists also used the images to glean other variables such as mitotic activity, tumor grade, and histologic subtypes for some of the TCGA marker papers. The recently published sarcoma TCGA marker paper utilized automated feature extraction of nuclear properties for correlation with copy number load and genomic doubling (Cancer Genome Atlas Research Network, 2017). The cutaneous melanoma TCGA marker paper used a visual inspection of expert pathologists to assess the degree and pattern of lymphocytes in the frozen section images of the tissue going to the molecular platforms to correlate with other genomic and proteomic assessments of lymphocytic infiltrate and also directly with clinical outcome (Cancer Genome Atlas Network, 2015).…”

“…We apply this to the TCGA samples in a broad multi-cancer fashion. Only a few TCGA tumor types have been explored for TIL content based on feature extraction from histologic H&E images and in a more limited fashion (Rutledge et al, 2013; Cancer Genome Atlas Research Network, 2017). …”

Tumours composed of fat are no longer a simple diagnosis: an overview of fatty tumours with a spindle cell component

“…Soft tissue sarcomas are diverse mesenchymal malignancies that account for approximately 1% of adult solid tumours 1. Despite their rarity, they hold a diagnostic and intellectual mystique that transcends their relative infrequency under a general diagnostic pathologist’s microscope.…”

“…A recent paper details the results of whole-exome sequencing performed on 206 sarcomas, including 50 DDLs, all of which were defined by 12q13-15 amplifications, including highly recurrent copy-number gains or amplification of MDM2 (100% of samples), CDK4 (92%) and HMGA2 (76%), as well as FRS2 (96%) and NAV3 (60%) 1. Other frequent somatic copy-number alterations involved genes reported to inhibit adipocyte differentiation, namely PTPRQ (46%), JUN (42%), DDIT3 (32%), CEBPA (24%) and YAP1 (16%).…”