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

Area of Science:

• Pediatric Oncology
• Cancer Genomics
• Molecular Pathology

Background:

• Some neuroblastoma patients initially classified as non-high-risk exhibit aggressive disease and poor survival.
• Identifying molecular drivers is crucial for understanding this discrepancy.

Purpose of the Study:

• To identify molecular aberrations at diagnosis that predict a high-risk clinical course in non-high-risk neuroblastoma patients.
• To investigate the role of segmental chromosomal aberrations (SCAs) and telomere maintenance mechanisms (TMMs).

Main Methods:

• Analysis of SCAs, gene amplifications, mutations, and TMMs in 89 non-high-risk neuroblastoma patients diagnosed between 2014-2021.
• Utilized single-nucleotide polymorphism array, next-generation sequencing, and FISH, WGS, RNA sequencing.
• Multiple imputation was used for SCA counts.

Main Results:

• An SCA profile (≥1 SCA) was significantly more frequent in patients with a high-risk course (76% vs 15%, p=0.004).
• 1p deletion (p=0.034), gains of 1q, 2p, 17q, deletions of 4p, 11q, and higher SCA counts were associated with high-risk outcomes.
• Alternative lengthening of telomeres (ALT) was activated in 57% of high-risk patients, and MDM2/CDK4 amplification was observed in two cases.

Conclusions:

• SCA profile and 1p deletion are significant predictors of a high-risk clinical course in neuroblastoma.
• ALT activation, MDM2/CDK4 co-amplification, and specific SCAs warrant further investigation as potential biomarkers for risk stratification.