New Study Reveals Prognostic Signature for High-Risk Neuroblastoma
Neuroblastoma, a type of cancer that affects children, is responsible for 15% of all childhood cancer-related deaths. While the overall survival rate for neuroblastoma patients has been improving over the years, high-risk neuroblastoma patients still face a survival rate of less than 50%. However, a new study has shed light on a potential prognostic signature that can help identify high-risk patients and potentially improve their treatment outcomes.
Using gene expression microarrays, researchers have identified a group of proteins known as snoRNPs whose expression levels correlate with poor prognosis in neuroblastoma patients. These snoRNPs are involved in regulating telomerase activity in neuroblastoma cells. When the researchers suppressed the expression of snoRNPs, they noticed an increase in anaphase bridge formation, a sign of elevated genetic instability. On the other hand, examination of genes associated with good prognosis revealed the involvement of genes related to growth cone formation.
Combining the expression of growth cone-associated genes with snoRNPs led to the development of a 4-gene prognostic signature. What’s interesting is that by calculating the ratio, known as the R-score, between the expression of good and bad prognostic genes, the need for housekeeper normalization was eliminated. This ratio-based approach provided a means of analyzing individual patients and evaluating their prognosis.
To test the effectiveness of the prognostic signature, the researchers applied a fixed-value R-score to three independent patient cohorts using standard quantitative PCR. The results not only confirmed the functionality of the R-score on an individual patient basis but also identified a subgroup of high-risk patients with ultra-high risk who could potentially benefit from new treatment modalities.
Among high-risk neuroblastomas, there is a subgroup of patients with MYCN amplification. The study further revealed that these MYCN-amplified tumors exhibit elevated expression of the miR-17-92 cluster of miRNAs. High-throughput proteomic analysis of cells overexpressing miR-17-92 uncovered the enrichment of the TGF-β pathway. Additional analyses showed that miR-17-92 targets and inhibits the TGF-β pathway at multiple levels, resulting in increased tumorigenic capacity of neuroblastoma cells.
Furthermore, the researchers investigated the role of hypoxia in neuroblastoma by studying breast cancer cells. They found that hypoxia induces the expression of the Notch-ligand JAG2, and decreased JAG2 expression in hypoxic tumor cells reduced the capacity of neighboring endothelial cells to form tubes. Similar findings were observed in neuroblastoma, albeit with the involvement of another Notch-ligand, DLL1. These results highlight the existence of Notch-ligand dependent crosstalk between tumor and endothelial cells in neuroblastoma.
In conclusion, this comprehensive study focused on high-risk patients and explored key signaling pathways involved in the maintenance and progression of neuroblastoma. It also introduced a novel prognostic signature that has significant clinical implications for high-risk patients. By providing insights into the molecular mechanisms and potential treatment targets, this research opens doors for personalized and targeted therapies that could improve outcomes for neuroblastoma patients, particularly those with high-risk disease.
