TY - JOUR
T1 - Urinary 3-Methoxytyramine Is a Biomarker for MYC Activity in Patients With Neuroblastoma
AU - Verly, Iedan R. N.
AU - Matser, Yvette A. H.
AU - Leen, René
AU - Meinsma, Rutger
AU - Fiocco, Marta
AU - Koster, Jan
AU - Volckmann, Richard
AU - Savci-Heijink, Dilara
AU - Cangemi, Giuliana
AU - Barco, Sebastiano
AU - Valentijn, Linda J.
AU - Tytgat, Godelieve A. M.
AU - van Kuilenburg, André B. P.
N1 - Funding Information: Supported by a grant from the Villa Joep Foundation and the Childhood Cancer Center Amsterdam Foundation. Publisher Copyright: © 2022 by American Society of Clinical Oncology
PY - 2022
Y1 - 2022
N2 - PURPOSE Elevated urinary 3-methoxytyramine (3MT) level at diagnosis was recently put forward as independent risk factor for poor prognosis in neuroblastoma. Here, we investigated the biologic basis underlying the putative association between elevated 3MT levels and poor prognosis. METHODS Urinary 3MT levels and prognosis were investigated in both retrospective Italian (N = 90) and prospective Dutch (N = 95) cohorts. From the Dutch Cancer Oncology Group cohort (N = 122), patients with available urinary 3MT and gene expression data (n = 90) were used to generate a 3MT gene signature. The 3MT gene signature score was then used to predict survival outcome in the Children's Oncology Group (N = 247) and German Pediatric Oncology Group (N = 498) cohorts and compared with other known gene signatures. Immunohistochemistry of MYCN and dopamine β-hydroxylase proteins was performed on primary tumors. RESULTS Elevated urinary 3MT levels were associated with poor prognosis in a retrospective cohort and a prospective cohort. Moreover, elevated urinary 3MT levels were associated with eight differentially expressed genes, providing a 3MT gene signature that successfully predicted poor clinical outcome. Even among low-risk patients, high 3MT signature score was associated with poor 5-year overall survival (72% v 99% among low-risk patients with a low 3MT signature score), and the 3MT signature score was correlated with MYC activity in the tumor (R = 82%, P<.0001). Finally, a strong MYCN and weak dopamine β-hydroxylase staining of tumors derived from patients with elevated urinary 3MT levels was observed, linking MYC activity in the tumor to both catecholamine biosynthesis and elevated urinary 3MT levels. CONCLUSION Elevated urinary 3MT is a promising biomarker for poor prognosis and reflects increased MYC activity in the tumor. Therefore, urinary 3MT levels should be measured at diagnosis and may assist in assessing risk.
AB - PURPOSE Elevated urinary 3-methoxytyramine (3MT) level at diagnosis was recently put forward as independent risk factor for poor prognosis in neuroblastoma. Here, we investigated the biologic basis underlying the putative association between elevated 3MT levels and poor prognosis. METHODS Urinary 3MT levels and prognosis were investigated in both retrospective Italian (N = 90) and prospective Dutch (N = 95) cohorts. From the Dutch Cancer Oncology Group cohort (N = 122), patients with available urinary 3MT and gene expression data (n = 90) were used to generate a 3MT gene signature. The 3MT gene signature score was then used to predict survival outcome in the Children's Oncology Group (N = 247) and German Pediatric Oncology Group (N = 498) cohorts and compared with other known gene signatures. Immunohistochemistry of MYCN and dopamine β-hydroxylase proteins was performed on primary tumors. RESULTS Elevated urinary 3MT levels were associated with poor prognosis in a retrospective cohort and a prospective cohort. Moreover, elevated urinary 3MT levels were associated with eight differentially expressed genes, providing a 3MT gene signature that successfully predicted poor clinical outcome. Even among low-risk patients, high 3MT signature score was associated with poor 5-year overall survival (72% v 99% among low-risk patients with a low 3MT signature score), and the 3MT signature score was correlated with MYC activity in the tumor (R = 82%, P<.0001). Finally, a strong MYCN and weak dopamine β-hydroxylase staining of tumors derived from patients with elevated urinary 3MT levels was observed, linking MYC activity in the tumor to both catecholamine biosynthesis and elevated urinary 3MT levels. CONCLUSION Elevated urinary 3MT is a promising biomarker for poor prognosis and reflects increased MYC activity in the tumor. Therefore, urinary 3MT levels should be measured at diagnosis and may assist in assessing risk.
UR - http://www.scopus.com/inward/record.url?scp=85124176112&partnerID=8YFLogxK
U2 - https://doi.org/10.1200/PO.20.00447
DO - https://doi.org/10.1200/PO.20.00447
M3 - Article
C2 - 35085004
SN - 2473-4284
VL - 6
JO - JCO Precision Oncology
JF - JCO Precision Oncology
M1 - e2000447
ER -