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Neuroblastoma arises in early fetal development and its evolutionary duration predicts outcome
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Neuroblastoma arises in early fetal development and its evolutionary duration predicts outcome
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Journal Article
Neuroblastoma arises in early fetal development and its evolutionary duration predicts outcome
2023
Overview
Neuroblastoma, the most frequent solid tumor in infants, shows very diverse outcomes from spontaneous regression to fatal disease. When these different tumors originate and how they evolve are not known. Here we quantify the somatic evolution of neuroblastoma by deep whole-genome sequencing, molecular clock analysis and population-genetic modeling in a comprehensive cohort covering all subtypes. We find that tumors across the entire clinical spectrum begin to develop via aberrant mitoses as early as the first trimester of pregnancy. Neuroblastomas with favorable prognosis expand clonally after short evolution, whereas aggressive neuroblastomas show prolonged evolution during which they acquire telomere maintenance mechanisms. The initial aneuploidization events condition subsequent evolution, with aggressive neuroblastoma exhibiting early genomic instability. We find in the discovery cohort (
n
= 100), and validate in an independent cohort (
n
= 86), that the duration of evolution is an accurate predictor of outcome. Thus, insight into neuroblastoma evolution may prospectively guide treatment decisions.
Somatic evolutionary analysis of neuroblastoma, a pediatric tumor, proposes a common fetal time of origin. Notably, high-risk tumors exhibit early genomic instability and prolonged evolution, and this evolutionary duration predicts clinical outcomes.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 45/23
/ Animal Genetics and Genomics
/ Biomedical and Life Sciences
/ Fetuses
/ Genomes
/ Humans
/ Infant
/ Mitosis
/ Mutation
/ Tumors
