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Findings Support Prognostic Potential for Gene Signature in Some Forms of Rhabdomyosarcoma

NEW YORK (GenomeWeb) – Members of the Children's Oncology Group have generated evidence supporting the notion that a five-gene expression signature can help predict survival patterns for pediatric rhabdomyosarcoma cases lacking a fusion between the PAX and FOXO1 genes.

Researchers from the US, Switzerland, and the UK set out to test the prognostic potential of the previously described signature in 57 children who appeared to fall in an intermediate risk group. Their findings are slated to appear today in Clinical Cancer Research.

Findings from the study indicated that the expression signature, dubbed the MG5 score, was linked to event-free survival and overall survival patterns in fusion-free forms of pediatric rhabdomyosarcoma, raising the possibility of stratifying these groups to receive more or less aggressive treatment down the road.

"[I]t will be important to validate this signature in a larger cohort of patients in which the MG5 score is prospectively determined," first author Pooja Hingorani, a researcher with Phoenix Children's Hospital's Center for Cancer and Blood Disorders, said in a statement. "Second, it is not yet clear whether knowing the MG5 score will allow us to meaningfully improve therapy in either group."

Theoretically, though, she explained, "[i]f increased risk of relapse or progression could be identified upfront, treatment might be intensified. Conversely, for patients who are identified as having a decreased risk of relapse or progression, we might be able to decrease their therapy and minimize toxicity."

Although rare overall, rhabdomyosarcoma is the most common form of soft tissue sarcoma affecting children and adolescents, Hingorani and co-authors explained. In the past, researchers have detected a PAX-FOXO1 gene fusion that provides prognostic clues for children with the alveolar histological subtype of rhadcomyosarcoma.

In tumors without this gene fusion, there have been hints that the expression of five genes — EPHA2, EED, NSMF, CBS, and EPB41L4B — might help in distinguishing those at highest risk from those with longer survival outcomes.

In an effort to independently test the prognostic value of those five genes, the researchers used NanoString Technologies' nCounter assay to assess expression patterns at 83 transcripts in formalin-fixed paraffin-embedded primary tumor samples from dozens of children with fusion-negative rhabdomyosarcoma who were enrolled in the COG D9803 clinical trial.

After tossing out duplicated samples, they were left with data for 57 fusion-negative rhabdomyosarcoma samples, including four-dozen samples from the embryonal histological subtype, six from the alveolar subtype, and three samples showing mixed features.

To explore potential ties between the MG5 expression signature and prognostic patterns, the team went on to assess MG5 scores in the context of event-free survival and overall survival patterns after three years and five years.

Consistent with the trend in the study where MG5 was first detected, Hingorani and colleagues saw extended survival times in children with fusion-negative rhabdomyosarcoma who had low MG5 expression scores relative to those with high MG5 scores.

The researchers found that the 20 individuals in the high MG5 score, high-risk group relapsed six times more often than their 37 low MG5 score counterparts, for example.

Likewise, their results suggest that overall survival rates are significantly lower in those with high MG5 score, both at the three- and five-year marks. In general, overall survival rates were roughly seven times lower in the fusion-negative rhabdomyosarcoma patients with elevated MG5 expression.

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