Different patterns of clonal evolution among different sarcoma subtypes followed for up to 25 years

Abstract

To compare clonal evolution in tumors arising through different mechanisms, we selected three types of sarcoma—amplicon-driven well-differentiated liposarcoma (WDLS), gene fusion-driven myxoid liposarcoma (MLS), and sarcomas with complex genomes (CXS)—and assessed the dynamics of chromosome and nucleotide level mutations by cytogenetics, SNP array analysis and whole-exome sequencing. Here we show that the extensive single-cell variation in WDLS has minor impact on clonal key amplicons in chromosome 12. In addition, only a few of the single nucleotide variants in WDLS were present in more than one lesion, suggesting that such mutations are of little significance in tumor development. MLS displays few mutations other than the FUS-DDIT3 fusion, and the primary tumor is genetically sometimes much more complex than its relapses, whereas CXS in general shows a gradual increase of both nucleotide- and chromosome–level mutations, similar to what has been described in carcinomas.

Genomic and transcriptomic features of dermatofibrosarcoma protuberans: Unusual chromosomal origin of the COL1A1-PDGFB fusion gene and synergistic effects of amplified regions in tumor development

“…We also had the opportunity to study two separate lesions, a primary tumor and its metastasis 6 years later, with WES. In line with previously published results on other soft tissue sarcomas [38] , neither the mutational load nor the extent of the amplified regions showed much variation with time or disease progression. Thus, it may well be that tumor progression in DPFT is largely driven by epigenetic changes.…”

“…Differences between tumor types in log2-transformed expression data were calculated using a t -test, and corrections for multiple testing were based on the Benjamini-Hochberg method (Qlucore AB). The two tumor samples and peripheral blood from Case 28 were analyzed by WES (Illumina, San Diego, CA, USA), with targeted resequencing for seven of the mutations detected at WES ( Table 1 ); these analyses were performed as described [37,38] . WES and targeted resequencing generated an average coverage of 99X and 145X, respectively.…”

The FUS-DDIT3 Interactome in Myxoid Liposarcoma

“…An alternative strategy that might confer less toxicity would be to target functionally important protein interacting partners of FUS-DDIT3. To date, genomic profiling at the RNA expression or exome level has revealed a low frequency of secondary genetic alterations [18], [19], [20]. While there have been individual reports of FUS-DDIT3 interactors, including CCAAT/enhancer-binding protein β (C/EBPβ) [21], [22], cyclin-dependent kinase 2 (CDK2) [23], NFKB inhibitor zeta (NFKBIZ) [9], RNA polymerase II [24], and all three FET proteins [25], the lack of comprehensive data on the FUS-DDIT3 interactome represents one of the major gaps in knowledge behind the oncogenic functions of the fusion protein.…”

DIscBIO: a user-friendly pipeline for biomarker discovery in single-cell transcriptomics

“…The MLS notebook is available at https://nbviewer.jupyter.org/github/ocbe-uio/DIscBIO/blob/dev/notebook/DIscBIO-MLS-Binder.ipynb. Myxoid liposarcoma (MLS) is a rare type of tumor driven by specific fusion oncogenes, normally FUS-DDIT3 [70,71], with few other genetic changes [72,73]. The 94 single cells were collected based on their cell cycle phase (G1, S or G2/M), assessed in the collection step by analyzing their DNA content using Fluorescence Activated Cell Sorter [74].…”