Abstract
Undifferentiated sarcomas (USARC) of adults are diverse, rare and aggressive soft tissue cancers. Recent efforts have confirmed that USARC exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the genomic basis of this structural complexity by integrating whole genome sequencing, ploidy analysis and methylation profiling of 53 USARC. We identified whole genome doubling as a prevalent and pernicious force in USARC tumourigenesis. Deconvolution of the complex copy number and rearrangement landscapes show distinct signatures associated with chromothripsis, early-haploidy, and successive whole-genome-doubling events, suggesting four divergent models of sarcoma development. We show similar distinct evolutionary tumourigenic pathways in different sarcoma subtypes from the Cancer Genome Atlas. Thirteen percent of tumours exhibited a hypermutator phenotype, opening new avenues for clinical management such as immunotherapy, whilst the period prior to and between genome doubling events may represent clinically relevant interventional points in USARC.
Highlights
Undifferentiated sarcomas (USARCs) of adults are soft tissue tumors that are among the most karyotypically complex of all cancers (TCGA, 2017)
To determine if molecularly defined subgroups could be identified in USARCs, we performed genome-wide methylation profiling (EPIC array) and gene expression analysis (RNA sequencing, Table S1) for all tumor samples for which sufficient high-quality nucleic acid was available
Compared with adjacent normal tissues USARC methylomes showed relative hypomethylation on a genome-wide scale with the majority of the signal confined to intergenic regions of the genome and in ‘‘open sea’’ regions rather than in promoter regions or CpG islands (Figure 1C), and this result was reproduced in the The Cancer Gene Atlas (TCGA).USARC dataset (Figure S1A)
Summary
Undifferentiated sarcomas (USARCs) of adults are soft tissue tumors that are among the most karyotypically complex of all cancers (TCGA, 2017). These tumors were previously known as malignant fibrous histiocytomas but historically have had multiple designations based on advances in diagnostic criteria (Fletcher, 2014). They are diagnosed by exclusion of other sarcoma entities and likely represent a final common morphological endpoint of a variety of sarcomas and, possibly, other tumors (Fletcher et al, 2001). A lack of objective diagnostic criteria has led to a dearth of studies interrogating genomic complexity
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