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European Study Suggests mRNA Signature Could Be Useful Prognostic in Neuroblastoma

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Researchers from several European institutions have used a clinical trial of children with stage IV neuroblastoma to test prospectively whether varying levels of several mRNA markers could stratify patients according to their outcomes. They hope that such an approach could be used to predict prognosis and guide treatment decisions for children with this cancer.

The study, published this month in the Journal of Clinical Oncology, confirmed that blood and bone marrow levels of three neuroblastoma mRNAs the group targeted were indeed predictive of patients' outcomes. Specifically, high levels of two of the markers, TH and PHOx2B, in patients' blood samples at diagnosis could be used to define a subset of children with what the group deemed "ultrahigh-risk disease."

According to the authors, the results indicate that a blood test based on these mRNAs could be a simple and useful tool, potentially in conjunction with additional genetic and other molecular markers, to predict which children fall into this ultrahigh-risk subset, and thus might benefit from more aggressive or experimental treatment approaches than standard induction therapy, which involves chemotherapeutics and surgical resection.

"The predictive power of these mRNAs at diagnosis reveals how their quantification could be used to identify upfront children with stage IV disease for whom current treatment is failing and who may be candidates for alternative, novel experimental therapeutics," the authors wrote.

According to the researchers, they and other groups have demonstrated previously that measuring levels of neuroblastoma-associated mRNA in the blood or bone marrow of patients could predict outcomes, but due to the small number of children studied and methodological differences among these previous retrospective studies, the clinical utility of such an approach has remained controversial.

With this new effort, the team hoped to put more persuasive, prospective evidence behind their findings. In the study, the group measured levels of the three mRNAs —TH, PHOX2B, and DCX — using a quantitative PCR approach on samples of blood and bone marrow from a cohort of 290 children, and also in blood samples from a second validation set of 175 children recruited later into the trial, both at the time of diagnosis, and after therapy.

According to the authors, high levels of all three mRNAs at the time of diagnosis strongly predicted worse outcomes for children in the study, both in terms of the kids' event-free survival and their overall survival. This association was also strong when looking at the patients' bone marrow post-therapy, but not for their peripheral blood samples post-therapy, the researchers wrote.

Narrowing toward a clinical use for the approach, the group showed that high levels of TH or PHOX2B in blood samples identified a subset of about 20 percent of the children in the study as having ultrahigh-risk disease, with five-year overall and event-free survival rates of zero percent, compared to 25 percent overall survival and almost 40 percent event-free survival among the remaining children.

The study authors did not respond by publication time to questions about what experimental therapeutic procedures clinicians might be able to choose for their patients based on molecular testing results indicating which patients will have a worse or better prognosis.

But identifying subgroups with especially poor prognosis among high-risk stage IV neuroblastoma patients could potentially help clinicians recruit patients least likely to benefit from current treatment strategies into clinical trials of nonstandard chemotherapies or other drug regimens.

According to the study authors, because levels of the mRNAs they looked at also remained predictive in patients' bone marrow after treatment, they could potentially also be used to track disease status and response to therapy in real time, with high expression of the mRNAs being an indicator of failure of current induction therapy.

However, using statistical methods, the team found that mRNA levels post-treatment did not add to the predictive power of either TH or PHOX2B levels pre-treatment. The clinical implication of this, the authors wrote, is mRNA levels at diagnosis appear to be the strongest indicator of outcome, and thus the best tool for potentially choosing a treatment strategy.

Clinicians, according to the study data, might be better served in deciding how to treat patients based on mRNA levels at diagnosis, rather than initiating standard treatment and then using post-treatment mRNA levels to modify their therapeutic strategy.

Before these markers could find clinical use though, the authors wrote that their predictive value will need to be confirmed and shown to be thoroughly independent of other clinical factors.

According to the group, international studies are currently underway comparing PCR measurement of these mRNAs with other potential prognostics based on genomic markers, multigene expression signatures, as well as basic histology and cytology methods, in order to identify a strategy, or a combination of strategies, that most reliably identifies those with the highest risk and worst prognosis.

In the meantime, the researchers wrote that they believe their results bode well for the utility of these three mRNAs as an important contribution to determining prognosis and informing treatment choice for children with these aggressive neuroblastomas in the future.

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