Copy-Number Evolution Maintains Diversity during Breast Tumor Growth

Although many studies have investigated mechanisms that lead to aneuploidy and copy-number aberrations (CNA) in cancer, technical challenges with current methods have hindered analysis of copy-number evolution during tumor progression. To explore chromosome evolution in human triple-negative breast cancer (TNBC) tumors, Minussi, Nicholson, Ye, and colleagues developed a single-cell single-molecule DNA-sequencing method called acoustic cell tagmentation (ACT), a higher-throughput and cost-effective approach relative to many other single-cell DNA-sequencing protocols. ACT was implemented on eight human TNBC tumors (n = 9,765 cells), revealing that the tumor cells could be divided into 3 to 5 superclones that were each further divided into 7 to 22 subclones in each of the eight tumors. The ACT data was used to infer phylogenetic trees that represented evolution of clonal lineages in individual tumors and suggested that copy-number evolution continued to occur following the onset of primary tumor expansion. To evaluate models that describe ongoing CNA accumulation in tumor cells, mathematical modelling was applied, providing evidence for a process of CNA accumulation in which TNBC cells undergo an initial burst of genomic instability followed by a period of transient instability before returning to copy-number evolution at a baseline rate. The application of ACT was extended to human TNBC cell lines, in which the copy-number substructure was found to be representative of that of TNBC tumors. Notably, one TNBC cell line was subcloned into single daughter cells that were expanded for 19 cell doublings, revealing that tumor cells acquired about one CNA per four cell divisions and highlighting that isogenic subcloning can still lead to heterogeneous genotypes. In summary, this work not only describes a novel method of single-cell DNA-sequencing at high resolution but also provides evidence for a model in which breast cancer cells maintain subclonal diversity during primary tumor growth.

Minussi DC, Nicholson MD, Ye H, Davis A, Wang K, Baker T, et al. Breast tumours maintain a reservoir of subclonal diversity during expansion. Nature 2021 Mar 24 [Epub ahead of print].

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