3MT Gene Signature May Predict Poor Outcomes in Neuroblastoma

An elevated level of urinary 3-methoxytyramine (3MT) is tied to poor prognosis in pediatric neuroblastoma, according to research published in JCO Precision Oncology.1

Researchers also found that elevated 3MT levels were associated with 8 differentially expressed genes, providing a gene signature that correlated with an increase in MYC activity and poor survival outcomes.

Results from a previous study suggested that having an elevated urinary 3MT level (>2.9-fold change) at diagnosis is an independent predictor of poor outcomes in neuroblastoma.2 With the current study, researchers set out to confirm that association and investigate the biological factors underlying it.1

The researchers first assessed the association between urinary 3MT levels and event-free survival (EFS) or overall survival (OS) in 2 cohorts — a retrospective cohort of Italian patients (n=90) and a prospective cohort of Dutch patients (n=95).


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In the retrospective cohort, patients with elevated 3MT levels had a significant reduction in EFS (P =.012) and OS (P =.0044). Likewise, in the prospective cohort, both EFS (P =.0017) and OS (P =.0053) were significantly lower among patients with elevated 3MT.

The researchers then used data from a Dutch Cancer Oncology Group cohort (n=122) to establish a correlation between urinary 3MT levels and gene expression data. A comparison of gene expression profiles between patients with and without elevated 3MT revealed 8 differentially expressed genes (P <.001), which were used to establish a gene signature.

The signature consisted of 4 genes that were significantly downregulated in patients with elevated urinary 3MT levels (SRR, PLXNC1, FBXO30, and CHD5) and 4 genes that were significantly upregulated in these patients (UTP4, EEF1AKNMT, NCBP2AS2, and CA5BP1).

The researchers noted a strong positive correlation between 3MT signature scores and urinary 3MT levels (P <.0001), suggesting the gene signature score could serve as a surrogate marker for urinary 3MT levels.

To investigate the association between the gene signature and patient outcomes, the researchers used data from a Children’s Oncology Group cohort (n=24,715) and a German Pediatric Oncology Group cohort (n=498). In both cohorts, patients with a high 3MT signature score had significantly worse EFS and OS than patients with a low 3MT signature score (P <.001 for all).

An additional analysis of the German Pediatric Oncology Group cohort suggested that the 3MT signature score accurately predicted MYC activity in the tumor. And an analysis across multiple cohorts suggested that MYC activity is tied to catecholamine biosynthesis and elevated urinary 3MT levels.

“3MT is a promising biomarker for poor prognosis and reflects increased MYC activity in the tumor,” the researchers wrote. “Given the increasing availability of therapies that target MYC/MYCN signaling, analyzing urinary 3MT levels may help identify patients who would likely benefit from these therapies.”

Disclosures: This research was supported by grants from foundations. One study author declared an affiliation with Frame Therapeutics. Please see the original reference for a full list of disclosures.

Reference

  1. Verly IRN, Matser YAH, Leen R, et al. Urinary 3-methoxytyramine is a biomarker for MYC activity in patients with neuroblastoma. JCO Precis Oncol. Published online January 27, 2022. doi:10.1200/PO.20.00447
  2. Verly IRN, van Kuilenburgb ABP, Abeling NGGM, et al. 3-Methoxytyramine: An independent prognostic biomarker that associates with high-risk disease and poor clinical outcome in neuroblastoma patients. Eur J Cancer. 2018;90:102-110. doi:10.1016/j.ejca.2017.11.025

Source: Medical Bag https://www.medicalbag.com/home/medicine/neuroblastoma-3mt-gene-signature-tied-myc-activity-worse-outcomes/

General Pediatric Cancer