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Genetic expression may predict metastases risk, OS in Ewing’s sarcoma
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A set of genes involved in CXC4-pathway signaling appeared to serve as a positive marker for OS and EFS and a negative marker for metastases development among patients with Ewing’s sarcoma, according to study results.
Ewing’s sarcoma is the second most common bone sarcoma in children and young adults, according to study background.
“The introduction of multi-agent chemotherapy in combination with advancements in surgery and radiotherapy have improved the 5-year OS of patients with localized disease from less than 10% to 70% nowadays, irrespective of the type of classical Ewing's sarcoma specific translocation,” Pancras C.W. Hogendoorn, MD, PhD, MSc, professor of pathology at Leiden University Medical Center in the Netherlands, and colleagues wrote. “However, the OS drops to less than 30% when metastases are present at the time of diagnosis, which is the case in 15% to 30% of new presentations, or with tumor relapse.”
Hogendoorn and colleagues sought to identify novel predictive biomarkers for patients who may be at risk for poor outcomes. They focused specifically on genes involved in the CXCR4-pathway due to their recognized role in metastasis and tumor growth.
The researchers used total RNA isolated from therapy-naive tumor samples (n = 18) and cell lines (n = 21) to study the expression of CXCR4-pathway related genes, as well as small (CXCR4-2) and large (CXCR4-1) splice variants.
Researchers correlated expression levels with OS and EFS, using an independent series of 26 therapy-naive tumor samples.
Overall, high CXCL7 and CXCL14 expression appeared positively associated with OS and EFS but negatively associated with metastasis development.
Further, both splice variants of CXCR4 were expressed in tumor samples and cell lines. The CXCR4-1/CXCR4-2 ratio appeared significantly higher in tumor samples than cell lines (median 0.03 vs. 0.012; P ˂ .001) and correlated with improved EFS and OS (P ˂ .03 for both).
The independent sample pattern validated the study findings.
“Here we document that the increased expression of genes involved in the down regulation of CXCR4 signaling and the CXCR4 splice variant balance predict the prognosis of therapy-naive patients with Ewing's sarcoma," Hogendoorn and colleagues wrote. “In addition, the CXCR4-1/CXCR4-2 ratio, the level of CXCR14 and the level of CXCR7 may be used as markers for therapeutic inhibition of the CXCR4 pathway. Based on our results, additional studies to further characterize the role of altered CXCR14, CXCR7 and CXCR4-1/CXCR4-2 ratio in CXCR4 signaling could be performed in model systems, such as well-established zebrafish models.” – by Cameron Kelsall
Disclosure: The researchers report no relevant financial disclosures.
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