Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns
Open Access
- 1 July 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 53 (8), 1187-1195
- https://doi.org/10.1038/s41588-021-00891-2
Abstract
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.Keywords
Funding Information
- ERC starting grant (IntratumoralNiche) and Health Holland grant
- Wellcome Trust (097319/Z/11/Z, 202778/Z/16/Z, 202778/Z/16/Z, 097319/Z/11/Z, 202778/B/16/Z, 202778/Z/16/Z)
- Foundation for the National Institutes of Health (U54 CA217376, U54 CA217376, U54 CA217376)
- Cancer Research UK (A22909, A19771)
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