Molecular Features Associated with a High-Risk Clinical Course in Neuroblastomas Initially Diagnosed as Non-High-Risk

<b>Background/Objectives</b>: Some patients initially diagnosed with non-high-risk neuroblastoma follow a high-risk clinical course and have poor survival compared to those initially diagnosed with high-risk neuroblastoma. We aimed to identify molecular aberrations present at diagnosis that may explain the high-risk clinical course in this patient group. <b>Methods</b>: Data were collected from non-high-risk neuroblastoma patients diagnosed at our center between 2014 and 2021. Segmental chromosomal aberrations (SCAs), gene amplifications and mutations at diagnosis were detected by a single-nucleotide polymorphism array and next-generation sequencing. Telomere maintenance mechanisms (TMMs) were investigated using fluorescent in situ hybridization, whole genome sequencing (WGS) and RNA sequencing. SCA counts were imputed by using multiple imputation. <b>Results</b>: The total cohort included 89 patients. Thirteen patients developed a high-risk clinical course (group A) due to progression (n = 4), local relapse (n = 4), refractory disease (n = 3) or metastases (n = 2). Seventy-six patients followed a non-high-risk clinical course (group B). An SCA profile (≥1 SCA) was present in 76% of patients in group A and only 15% in group B (<i>p</i> = 0.004). 1p deletion was associated with a high-risk clinical course (<i>p</i> = 0.034). Gains of 1q, 2p and 17q, and deletions of 4p and 11q were more common in group A. After imputation, SCA count was associated with a high-risk clinical course (pooled OR 1.256 with 95% CI 1.006-1.568, <i>p</i> = 0.044). Two patients, both group A, exhibited <i>MDM2</i>/<i>CDK4</i> amplification. Alternative lengthening of telomeres (ALT) was activated in 57% of group A. <b>Conclusions</b>: SCA profile and 1p deletion are associated with a high-risk clinical course. ALT activation, <i>MDM2</i>/<i>CDK4</i> co-amplification, SCA count, gains of 1q, 2p, and 17q, and deletions of 4p and 11q may also be relevant molecular markers. Larger studies are needed for confirmation of these findings.