Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
08
03
2021
accepted:
24
05
2021
pubmed:
3
7
2021
medline:
11
9
2021
entrez:
2
7
2021
Statut:
ppublish
Résumé
Central to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq-a protocol that integrates live-cell imaging of tumor organoid outgrowth and whole-genome sequencing of each imaged cell to reconstruct evolving tumor cell karyotypes across consecutive cell generations. Using patient-derived colorectal cancer organoids and fresh tumor biopsies, we demonstrate that karyotype alterations of varying complexity are prevalent and can arise within a few cell generations. Sub-chromosomal acentric fragments were prone to replication and collective missegregation across consecutive cell divisions. In contrast, gross genome-wide karyotype alterations were generated in a single erroneous cell division, providing support that aneuploid tumor genomes can evolve via punctuated evolution. Mapping the temporal dynamics and patterns of karyotype diversification in cancer enables reconstructions of evolutionary paths to malignant fitness.
Identifiants
pubmed: 34211178
doi: 10.1038/s41588-021-00891-2
pii: 10.1038/s41588-021-00891-2
pmc: PMC8346364
doi:
Substances chimiques
Chromatin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1187-1195Subventions
Organisme : NCI NIH HHS
ID : U54 CA217376
Pays : United States
Organisme : Cancer Research UK
ID : A19771
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A22909
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 202778/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 097319/Z/11/Z
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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