From the Journals

Chromoplexy linked to aggressive Ewing sarcomas

Key clinical point: Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas.

Major finding: Chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 42% of Ewing sarcoma tumors.

Study details: A study of the whole genomes of 124 Ewing sarcomas.

Disclosures: This research project was conducted with support from C17 and partially funded by Ewings Cancer Foundation of Canada and Childhood Cancer Canada Foundation. The authors declared no competing interests.

Source: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.

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Time for whole genome sequencing in Ewing sarcoma?

The contribution of genetic analysis to the current standard of care for Ewing sarcoma is limited to confirmation of the diagnostic EWSR1-FLI1 or EWSR1-ERG fusions. The discovery of genomic patterns associated with subsets of Ewing sarcomas raises the question of whether additional molecular diagnostic modalities are warranted. If chromoplexy events are important clinical biomarkers for disease aggressiveness in this tumor, as the authors suggest, their findings may support a new indication for clinical whole genome sequencing.

Analysis of additional patient samples will be needed, however, to confirm that the presence of chromoplexy is an independent prognostic predictor in Ewing sarcoma. This is because the researchers find that chromoplexy-driven Ewing sarcoma more likely contains tumor protein 53 (TP53) mutations. Because TP53 and stromal antigen 2 (STAG2) mutations and genomic complexity have each been associated with more aggressive Ewing sarcoma, dissecting the contribution of these factors to poor clinical outcomes in chromoplexy-derived Ewing sarcoma will be an important area of future work.

More generally, the study has important clinical implications for the genomic diagnosis of these and other cancers, as well as the expanding biological role of complex rearrangements in cancer evolution.

Could chromoplexy events in Ewing sarcoma be linked, for example, to the activity of an aberrantly expressed endogenous transposase such as PiggyBac transposase 5 (PGBD5), which was recently implicated in the genesis of the pathogenic gene rearrangements in childhood malignant rhabdoid tumors? An alternative possibility is a constitutional or acquired DNA repair defect (Science 2018 Aug 31. doi: 10.1126/science.aau8231).

Marcin Imielinski is with the Meyer Cancer Center, Cornell University, and the New York Genome Center, New York. Marc Ladanyi is with Memorial Sloan Kettering Cancer Center, New York. They made their remarks in an editorial in Science that accompanied the study.


 

FROM SCIENCE

Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas, based on a study of 124 tumors reported in Science.

Ewing sarcomas with complex karyotypes are associated with a poorer prognosis compared with those with simpler karyotypes. The new findings show that these complex karyotypes are the product of chromoplexy, and that chromoplexy-generated fusions arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

Analysis of the sequence context surrounding chromoplexy breaks may provide clues and potentially point to a therapeutic vulnerability that could be used to treat Ewing sarcomas. Further, given the preference of chromoplexy events for transcriptionally active regions, Ewing sarcomas arising from chromoplexy may be responsive to immune checkpoint inhibition.

In a study of the whole genomes of 124 Ewing sarcomas, chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 52 tumors (42%). Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors.

“Our analyses reveal rearrangement bursts (chromoplectic loops) as a source of gene fusion in human bone and soft tissue tumors. Ewing sarcomas with complex karyotypes are associated with a poorer prognosis than those with simpler karyotypes, and here we show chromoplexy as the mechanism in 42% of tumors. It is possible that the chromoplectic tumor’s additional gene disruptions and fusions contribute to the difference in patient survival,” wrote Nathaniel D. Anderson of the Hospital for Sick Children, Toronto, and the University of Toronto, and his colleagues.

Standard reciprocal translocations involve DNA breaks in two fusion partners. Chromoplexy involves three or more breakpoints in the genome. A loop pattern emerges as these three or more broken chromosome ends are forced to find a new partner. The result is the formation of functional EWSR1-FLI1 or EWSR1-ERG fusions that, upon expression, provide a selective growth or survival advantage

The researchers found that the loop rearrangements always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions.

They found similar loops forming canonical fusions in three other sarcoma types.

“Our whole-genome sequence data support a model in which there is an early clone of (Ewing sarcoma), containing EWSR1-ETS and chromoplexy, arising at least 1 year before diagnosis, which gives rise to both the primary and metastatic or relapse tumors. Whether the bursts ... are chance events or driven by specific mutational processes, akin to the RAG machinery operative in leukemia, remains to be established. As an increasing and diverse number of tumor genome sequences become available, we may be able to define further rearrangement processes that underlie fusion genes and thus unravel the causes of fusion-driven human cancers,” the researchers wrote.

The clinical features and demographics of the study patients were typical of Ewing sarcoma patients. Average patient age at diagnosis was 14.8 years (2.8 to 36.6 years); the male to female ratio was 1.38:1; and 14 patients had relapsed, with 13 having died from their disease.

About half of fusions between the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22 and an E26 transformation-specific (ETS) family transcription factor gene, either FLI1 at 11q24 or ERG at 21q11 arose via chromoplexy.

SOURCE: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.

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