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Extensive clonal branching shapes the evolutionary history of high-risk pediatric cancers

Andersson, Natalie LU ; Bakker, Bjorn ; Karlsson, Jenny LU ; Valind, Anders LU ; Holmquist Mengelbier, Linda LU ; Spierings, Diana C J ; Foijer, Floris and Gisselsson, David LU (2020) In Cancer Research 80(7). p.1512-1523
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 was 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... (More)

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 was 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 to 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, while in Wilms tumor they are late events. Thus, from an evolutionary standpoint, some high-risk childhood cancers are born bad, while others grow worse over time.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
80
issue
7
pages
12 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:85082796762
  • pmid:32041836
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-19-3468
language
English
LU publication?
yes
additional info
Copyright ©2020, American Association for Cancer Research.
id
09b6b399-f30a-4f1e-b9e3-f33c4c750928
date added to LUP
2020-03-09 11:04:32
date last changed
2021-06-16 05:15:04
@article{09b6b399-f30a-4f1e-b9e3-f33c4c750928,
  abstract     = {<p>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 was 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 to 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, while in Wilms tumor they are late events. Thus, from an evolutionary standpoint, some high-risk childhood cancers are born bad, while others grow worse over time.</p>},
  author       = {Andersson, Natalie and Bakker, Bjorn and Karlsson, Jenny and Valind, Anders and Holmquist Mengelbier, Linda and Spierings, Diana C J and Foijer, Floris and Gisselsson, David},
  issn         = {1538-7445},
  language     = {eng},
  number       = {7},
  pages        = {1512--1523},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Extensive clonal branching shapes the evolutionary history of high-risk pediatric cancers},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-19-3468},
  doi          = {10.1158/0008-5472.CAN-19-3468},
  volume       = {80},
  year         = {2020},
}