Sarcoma-Associated Gene Fusions a Result of ‘Genome Chaos’


A study finds EWSR1-ETS in 42% of cases via complex, loop-like rearrangements, rather than by simple reciprocal translocations.

Many Ewing sarcomas are caused by chromosome misrepair events that occur years before diagnosis and yield cancer-driving gene rearrangements like the Ewing sarcoma breakpoint region 1 (EWSR1-ETS) gene fusion, according to a study published in the journal Science.

“We found that EWSR1-ETS, the key Ewing sarcoma fusion, arises in 42% of cases via complex, loop–like rearrangements called chromoplexy, rather than by simple reciprocal translocations,” reported senior study author Adam Shlien, PhD, of the University of Toronto, and co-authors.

The researchers sequenced the genomes of 124 Ewing sarcoma tumors, finding profound genomic reorganization in the chromoplexic tumors. They also identified chromoplexy–associated gene fusions in several other sarcoma types.

Ewing sarcoma has long been believed to be a very fast-growing tumor type. By using molecular “clocks” to analyze the divergence of primary and relapsed tumors, the authors concluded that chromoplexy events occur between 1–2 years before initial diagnosis.

Chromoplexy–associated gene fusion-harboring Ewing sarcomas were more aggressive than others, they authors reported.

Genomic alterations beyond the gene fusions likely plays an important role in that aggressiveness, according to Henry Heng, PhD, of the Center for Molecular Medicine and Genetics at the Wayne State University School of Medicine in Detroit.

“It is known that genomic instability functions as a key factor related to the aggressiveness of tumors,” Heng said. “The study further confirmed the importance of genome reorganization in cancer evolution.”

Chromoplexy is just one form of “genome chaos” that has been linked to various malignancies, according to Heng. “These chromosomal alterations involve all of the major cancer transitions, including transformation, metastasis and drug resistance,” said Heng.

Damon Reed, MD, program leader, Adolescent Young Adult Program at Moffitt Cancer Center in Tampa, Florida believes the study is exciting.

“There is something about sarcoma biology that we still don't understand and I think this study gives us a little bit more insight into it,” Reed said. “Sarcomas are not melanoma. Melanoma is a lot of mutations and one of them in more than half the time it is BRAF V600E mutation. That's not true in sarcomas--we don't have our BRAF.”

The study findings hint that “there's probably something fundamental going on in the nuclei with DNA repair in sarcoma," Reed said.

“[The results] confirm our suspicion that relapses don’t really have much to do with-and probably diverged quite early from-the primary tumor we’re facing,” Reed explained. “When we shrink primary tumors we always feel good and patients are happy-but it has nothing to do with outcomes. I think that poses some fundamental questions to the way we approach sarcoma.”

Because sarcomas are so rare, the findings probably do not represent a viable screening tool for early detection, Reed cautioned. But the findings do offer insight into the latency period of Ewing sarcoma, which is frequently important to patients and their families, he said.

“Just earlier today, the parents of a young adult with cancer asked me, when 'did this cancer start?'” he said. “It's important to them. I used to have no good answer to that."

Recent Videos
Experts from Vanderbilt University Medical Center emphasize gathering a second opinion to determine if a tumor is resectable in patients with pancreatic cancer.
A panel of 4 experts on multiple myeloma
A panel of 4 experts on multiple myeloma
Experts from Vanderbilt University Medical Center discuss the use of intraoperative radiation therapy in a 64-year-old patient with pancreatic cancer.
Balazs Halmos, MD, with the Oncology Brothers presenting slides
Balazs Halmos, MD, with the Oncology Brothers presenting slides
Balazs Halmos, MD, with the Oncology Brothers presenting slides
Balazs Halmos, MD, with the Oncology Brothers presenting slides
Balazs Halmos, MD, with the Oncology Brothers presenting slides
Although no responses were observed in 11 patients receiving abemaciclib monotherapy, combination therapies with abemaciclib may offer clinical benefit.
Related Content