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Subset of Ewing Sarcomas Arise from Early, Complex Genome Rearrangements

NEW YORK (GenomeWeb) – A subset of particularly aggressive Ewing sarcomas seem to stem from a complex rearrangement known as chromoplexy that occurs early in cancer development, long before tumors appear, new research suggests.

As they reported online today in Science, investigators from the Hospital for Sick Children (SickKids), the University of Toronto, the Wellcome Trust Sanger Institute, and elsewhere used exome sequencing, whole-genome sequencing, or RNA sequencing to explore the molecular events leading to characteristic EWSR1-ETS gene fusions in Ewing sarcoma, a form of bone and soft tissue cancer typically diagnosed in adolescents or young adults.

Across tumor samples from 124 individuals with Ewing sarcoma, the team uncovered 52 that showed telltale "loop-like" rearrangements stemming from chromoplexy. The analyses suggested these rearrangements lead to fusions such as EWSR1-ETS, while disrupting several other genes — perhaps explaining the apparent ties between chromoplexy and Ewing sarcoma aggressiveness that the group detected.

"We found dramatic early chromosomal shattering in 42 percent of Ewing sarcomas, not only fusing two critical genes together, but also disrupting a number of important areas," co-corresponding author Adam Shlien, co-director of the SickKids Cancer Sequencing program and associate director of translational genetics, said in a statement.

In follow-up experiments, he and his colleagues saw signs of chromoplexy in three more bone or soft tissue tumor types, including chondromyxoid fibroma, synovial sarcoma, and phosphaturic mesenchymal tumors.

At the American Association for Cancer Research annual meeting in Chicago this spring, Shlien presented data from the "Precision Oncology for Young People" (PROFYLE) project, including the complicated rearrangements found in Ewing sarcoma and other sarcoma cases.

The team began by sequencing the exomes of matched tumor and normal samples from 27 Ewing sarcoma cases and the genomes of another 23 matched tumor-normal pairs, searching for somatic mutations and rearrangements in the tumors.

As reported in past genomic studies, the Ewing sarcomas tended to be "genetically quiet," the researchers found, despite the multiple mutational signatures that turned up in the tumors. On the rearrangement side, though, the breakpoint data pointed to clustered, complex, looping rearrangements that "nearly always centered on EWSR1-ETS."

The team saw still more examples of these complex rearrangements using genome sequence data for 100 more Ewing sarcoma patients, along with genome and transcriptome sequences from individuals with other bone and soft tissue tumor types.

In Ewing sarcoma, the researchers noted that patient outcomes are typically worse when their tumors are more complex — a notion supported by the presence of chromoplexy in half a dozen advanced or secondary tumors assessed for the current study. Because their follow-up analyses pointed to chromoplexy as an early event in tumor development, the investigators speculated that the rearrangement might ultimately help in finding chromoplexy-related sarcomas early on.

"In principle, this study provides evidence that Ewing sarcoma could be detectable earlier, possibly even before it reveals itself as disease," co-corresponding author Sam Behjati, a pediatrics researcher affiliated with the Sanger Institute and the University of Cambridge, said in a statement.

"If we could detect these childhood cancers sooner, when tumors are smaller, they would be much easier to treat," Behjati added. "Further research is needed, but this possibility of finding a way to diagnose Ewing sarcomas earlier could help patients in the future."