Extensive clonal branching shapes the evolutionary history of high-risk pediatric cancers
(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.
(Less)
- author
- 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
- organization
- publishing date
- 2020-04
- 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
-
- pmid:32041836
- scopus:85082796762
- 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
- 2023-12-04 09:35:17
@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}}, }