Wendy W. J. de Leng

Background/Objectives: 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. Methods: 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. Results: 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 (p = 0.004). 1p deletion was associated with a high-risk clinical course (p = 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, p = 0.044). Two patients, both group A, exhibited MDM2/CDK4 amplification. Alternative lengthening of telomeres (ALT) was activated in 57% of group A. Conclusions: SCA profile and 1p deletion are associated with a high-risk clinical course. ALT activation, MDM2/CDK4 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.

Correlation between TMB and other baseline characteristics

Representativeness of study population

Baseline characteristics of evaluable patients treated with nivolumab + ipilimumab, stratified by objective response

Genetic immune escape landscape and driver alterations

Supplementary Table S6 from Checkpoint Blockade Combinations in Tumor Mutational Burden/Load-High Tumors: Insights from the Atezolizumab + Bevacizumab and Nivolumab + Ipilimumab Cohorts in the Drug Rediscovery Protocol