Extensive Clonal Branching Shapes the Evolutionary History of High-Risk Pediatric Cancers

Abstract

Darwinian evolution of tumor cells remains underexplored in childhood cancer. We here reconstruct the evolutionary histories of 56 pediatric primary tumors, including 24 neuroblastomas, 24 Wilms tumors, and 8 rhabdomyosarcomas. Whole-genome copy-number and whole-exome mutational profiling of multiple regions per tumor were performed, followed by clonal deconvolution to reconstruct a phylogenetic tree for each tumor. Overall, 88% of the tumors exhibited genetic variation among primary tumor regions. This variability typically emerged through collateral phylogenetic branching, leading to spatial variability in the distribution of more than 50% (96/173) of detected diagnostically informative genetic aberrations. Single-cell sequencing of 547 individual cancer cells from eight solid pediatric tumors confirmed branching evolution to be a fundamental underlying principle of genetic variation in all cases. Strikingly, cell-to-cell genetic diversity was almost twice as high in aggressive compared with clinically favorable tumors (median Simpson index of diversity 0.45 vs. 0.88; P = 0.029). Similarly, a comparison of multiregional sampling data from a total of 274 tumor regions showed that new phylogenetic branches emerge at a higher frequency per sample and carry a higher mutational load in high-risk than in low-risk tumors. Timelines based on spatial genetic variation showed that the mutations most influencing relapse risk occur at initiation of clonal expansion in neuroblastoma and rhabdomyosarcoma, whereas in Wilms tumor, they are late events. Thus, from an evolutionary standpoint, some high-risk childhood cancers are born bad, whereas others grow worse over time. Significance: Different pediatric cancers with a high risk of relapse share a common generic pattern of extensively branching evolution of somatic mutations.

Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma

“…In the metastasis, as suggested by the fewer CNAs observed in the orbit with respect to the lymph node samples and the divergence of somatic mutations, the dissemination niche also contributed to further evolution. This interpretation is consistent with the recently published evidence that different pediatric solid cancers relapses share a common generic pattern of clonal expansion and evolution of somatic genomic changes, in which high risk aberrations, such as MYCN amplification in neuroblastoma and TP53 in Wilms tumor lead to complex chromosome changes and anaplastic histological features [48]. Other aberrations, such as the OTX2 amplification in the lymph node sample [11,49] and the 11p deletion in the orbital metastasis (aberration mainly described in Wilms tumors in children [50]), may be contributing to the phenotypes, although no clear association could be established.…”

The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

“…Druggable events vary between primary and relapse tumors. Only 37% of primary tumors retained these events upon progression whilst most tumors gained events, as reported in disease-specific reports [32,33,[77][78][79][80][81][82][83][84] These substantial spatiotemporal differences in the molecular profiles of multiple samples acquired from the same patient as well as metastases compared to primary tumors indicate the need for subsequent analyses to optimize biomarker-driven selection in clinical trial recruitment [39].…”

Understanding tumour cell heterogeneity and its implication for immunotherapy in liver cancer using single-cell analysis

“…41 To understand and follow clonal evolution, single-cell analysis is an unprecedented tool. [42][43][44] Beyond a deeper understanding of cancer evolution, the decomposition of heterogenous cellular populations and the analysis of rare cell populations will further enhance our understanding of intratumoural driver processes. 34 The identification of rare subpopulations, such as cancer stem cells or cancer initiating cells, is an important goal and might provide a fundamental explanation of cancer development or treatment failure.…”