Untargeted LC-HRMS Based-Plasma Metabolomics Reveals 3-O-Methyldopa as a New Biomarker of Poor Prognosis in High-Risk Neuroblastoma

Abstract

Neuroblastoma (NB) is the most common extracranial malignant tumor in children. Although the survival rate of NB has improved over the years, the outcome of NB still remains poor for over 30% of cases. A more accurate risk stratification remains a key point in the study of NB and the availability of novel prognostic biomarkers of “high-risk” at diagnosis could help improving patient stratification and predicting outcome.In this paper we show a biomarker discovery approach applied to the plasma of 172 NB patients. Plasma samples from a first cohort of NB patients and age-matched healthy controls were used for untargeted metabolomics analysis based on high-resolution mass spectrometry (HRMS). Differential expression analysis highlighted a number of metabolites annotated with a high degree of identification. Among them, 3-O-methyldopa (3-O-MD) was validated in a second cohort of NB patients using a targeted metabolite profiling approach and its prognostic potential was also analyzed by survival analysis on patients with 3 years follow-up. High expression of 3-O-MD was associated with worse prognosis in the subset of patients with stage M tumor (log-rank p < 0.05) and, among them, it was confirmed as a prognostic factor able to stratify high-risk patients older than 18 months. 3-O-MD might be thus considered as a novel prognostic biomarker of NB eligible to be included at diagnosis among catecholamine metabolite panels in prospective clinical studies. Further studies are warranted to exploit other potential biomarkers highlighted using our approach.

Neuroblastoma is associated with alterations in gut microbiome composition subsequent to maternal microbial seeding

“…These metabolic changes are concordant with those detected in the only study available that compared plasma metabolome composition in patients with NB to healthy children. 62 Only one species, Enterobacter hormaechei (member of the Enterobacter clocae complex and reportedly a nosocomial pathogen), was found increased in patients, along with a more proteolytic functional profile. Such alterations were not detected in healthy siblings, which resembled the healthy nonkin group, and allowed validating most of the neuroblastoma-associated microbiome differences we found.…”

Small molecule metabolites: discovery of biomarkers and therapeutic targets

“… 577 One example comes from Barco et al, who used a targeted metabolite profiling approach to discover the high expression of 3-O-methyldopa was associated with worse prognosis in neuroblastoma patients. 578 A study performed untargeted metabolomics had revealed eight metabolic biomarkers were identified as prognostic biomarkers of acute ischemic stroke. 579 As an example according to Brunmair et al, metabolic phenotyping of tear fluid has been successfully established and revealed taurine and nicotinic acid represent new biomarkers were elevated in the diabetic cohort, and supports prediction of disease development.…”