Chromoplexy is a frequent early clonal event in EWSR1-rearranged round cell sarcomas that can be detected using clinically validated targeted sequencing panels Journal Article
| Authors: | Dermawan, J. K.; Slotkin, E.; Tap, W. D.; Meyers, P.; Wexler, L.; Healey, J.; Vanoli, F.; Vanderbilt, C. M.; Antonescu, C. R. |
| Article Title: | Chromoplexy is a frequent early clonal event in EWSR1-rearranged round cell sarcomas that can be detected using clinically validated targeted sequencing panels |
| 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. © 2024 American Association for Cancer Research Inc.. All rights reserved. |
| Keywords: | adolescent; adult; child; clinical article; controlled study; human tissue; bone neoplasms; middle aged; bone tumor; young adult; exon; genetics; clinical feature; cancer growth; genetic analysis; metastasis; cohort analysis; gene locus; genetic association; genetic variability; genetic variation; pathology; carcinogenesis; ewing sarcoma; gene rearrangement; gene fusion; fusion gene; oncogene proteins, fusion; chromosome breakage; chromosome rearrangement; chromosome translocation; chromosome deletion; rna binding protein ews; ewsr1 protein, human; desmoplastic small round cell tumor; genetic algorithm; rna-binding protein ews; ewsr1 gene; procedures; chromosome inversion; high throughput sequencing; high-throughput nucleotide sequencing; sarcoma, ewing; humans; human; male; female; article; whole exome sequencing; chromoplexy; structural variant; oncogene fusion protein; breakpoint allele fraction analysis |
| Journal Title: | Cancer Research |
| Volume: | 84 |
| Issue: | 9 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-05-01 |
| Start Page: | 1504 |
| End Page: | 1516 |
| Language: | English |
| DOI: | 10.1158/0008-5472.Can-23-2573 |
| PUBMED: | 38335254 |
| PROVIDER: | scopus |
| PMCID: | PMC11648190 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Christina Antonescu -- Source: Scopus |
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