The Evolutionary Duration of Neuroblastoma Predicts Clinical Outcome

Neuroblastoma demonstrates a wide spectrum of clinical outcomes, with certain characteristic mutations being associated with high-risk disease. However, the origination and evolution of low-risk versus high-risk tumors are not well understood. To evaluate the somatic evolution of neuroblastoma and its effects on disease severity and outcomes, Körber and colleagues conducted deep (approximately 80×) whole-genome sequencing, molecular clock analysis, and population-genetic modeling of a discovery cohort of 100 neuroblastoma tumors and showed that tumors across the clinical spectrum have clonal aneuploidy as an early feature of disease. Moreover, somatic single-nucleotide variants (SSNV) were used as a molecular clock to gain information on tumor evolution, which revealed the emergence of the most recent common ancestor cell (MRCA). Evaluation of the timing of the mutation densities indicated that the early common ancestor (ECA) is conserved across samples, while the timing of the MRCA demonstrated a bimodal distribution of clonal evolution, with one class of neuroblastoma in which growth commenced early (early-MRCA neuroblastoma) and a second class in which evolution was prolonged (late-MRCA neuroblastoma). Further investigation into these classes revealed that early-MRCA tumors have longer event-free and overall survival as compared to the late-MRCA class, suggesting that extended evolution predicts an unfavorable outcome. Additionally, different processes were found to underlie the early acquisition of aneuploidy between the two classes, specifically missegregation of entire chromosomes in early-MRCA and genomic instability in late-MRCA tumors. Late-MRCA tumors also had strong enrichment of telomere maintenance mechanisms through MYCN amplification, alternative lengthening of telomeres, or TERT locus rearrangement. Finally, these results were combined into an integrative model of tumor evolution that could infer the rate of SSNV acquisition, and use of this model revealed that the ECA can occur as early as the first trimester of pregnancy. In conclusion, this study reveals that the timing of neuroblastoma evolution accurately predicts clinical outcome and suggests that MRCA timing could be a useful parameter for patient stratification moving forward.

Körber V, Stainczyk SA, Kurilov R, Henrich KO, Hero B, Brors B, et al. Neuroblastoma arises in early fetal development and its evolutionary duration predicts outcome. Nat Genet 2023;55:619–30.

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