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Supplementary Figures S1-S12 from Chromoplexy Is a Frequent Early Clonal Event in EWSR1-Rearranged Round Cell Sarcomas That Can Be Detected Using Clinically Validated Targeted Sequencing Panels

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posted on 2024-05-02, 07:43 authored by Josephine K. Dermawan, Emily Slotkin, William D. Tap, Paul Meyers, Leonard Wexler, John Healey, Fabio Vanoli, Chad M. Vanderbilt, Cristina R. Antonescu

Figure S1. gGraphs depicting gWalk showing connectivities of chromoplectic structural variants (each represented by different color paths) to common nodes. Figure S2. Circos plots depicting the canonical and noncanonical structural variants detected in prostate carcinoma cases with TMPRSS2::ERG driver fusion. Figure S3. Inter- vs. intrachromosomal chromooplectic events among cases with EWSR1::FLI1, EWSR1::ERG or EWSR1::WT1 driver fusions. Figure S4. Longitudinal sequencing of sequential Ewing sarcoma (EWSR1::FLI1) cases illustrating structural variants, gene-level mutations and copy number variations, and arm-level chromosomal gains and losses. Figure S5. Longitudinal sequencing of sequential desmoplastic small round cell tumor (EWSR1::WT1) cases illustrating structural variants, gene-level mutations and copy number variations, and arm-level chromosomal gains and losses. Figure S6. Distribution of age among cases with EWSR1::FLI1, EWSR1::ERG or EWSR1::WT1 with or without chromoplexy. Figure S7. Heatmap and boxplot quantifying percentage genome with copy number variations among cases with EWSR1::FLI1, EWSR1::ERG or EWSR1::WT1 with or without chromoplexy. Figure S8. Frequency of chr8 gains among cases with EWSR1::FLI1, EWSR1::ERG or EWSR1::WT1 with or without chromoplexy. Figure S9. Kaplan-Meier curves for overall and progression-free survival in Ewing sarcoma with EWSR1::FLI1 versus EWSR1::ERG. Figure S10. Kaplan-Meier curves for overall and progression-free survival in Ewing sarcoma with or without chromoplexy. Figure S11. Kaplan-Meier curves for overall and progression-free survival in desmoplastic small round cell tumor with or without chromoplexy. Figure S12. Kaplan-Meier curves for overall and progression-free survival in all Ewing sarcoma cases with or without chr8 gains.

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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St. Baldrick's Foundation (SBF)

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ARTICLE ABSTRACT

Chromoplexy is a phenomenon defined by large-scale chromosomal chained rearrangements. A previous study observed chromoplectic events in a subset of Ewing sarcomas (ES), which was linked to an increased relapse rate. Chromoplexy analysis could potentially facilitate patient risk stratification, particularly if it could be detected with clinically applied targeted next-generation sequencing (NGS) panels. Using DELLY, a structural variant (SV) calling algorithm that is part of the MSK-IMPACT pipeline, we characterized the spectrum of SVs in EWSR1-fused round cell sarcomas, including 173 ES and 104 desmoplastic small round cell tumors (DSRCT), to detect chromoplexy and evaluate its association with clinical and genomic features. Chromoplectic events were detected in 31% of the ES cases and 19% of the DSRCT cases. EWSR1 involvement accounted for 76% to 93% of these events, being rearranged with diverse noncanonical gene partners across the genome, involving mainly translocations but also intrachromosomal deletions and inversions. A major breakpoint cluster was located on EWSR1 exons 8–13. In a subset of cases, the SVs disrupted adjacent loci, forming deletion bridges. Longitudinal sequencing and breakpoint allele fraction analysis showed that chromoplexy is an early event that remains detectable throughout disease progression and likely develops simultaneously with the driver fusion. The presence of chromoplexy was validated in an external ES patient cohort with whole exome sequencing. Chromoplexy was significantly more likely to be present in cases that were metastatic at presentation. Together, this study identifies chromoplexy as a frequent genomic alteration in diverse EWSR1-rearranged tumors that can be captured by targeted NGS panels. Chromoplexy is detectable using targeted NGS in a substantial portion of EWSR1-rearranged round cell sarcomas as an early and persistent clonal event, expanding the genomic complexity of fusion-associated sarcomas.

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    Cancer Research

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    Computational MethodsSequence analysisGenome BiologySarcomas

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