Breast tumours maintain a reservoir of subclonal diversity during expansion

Darlan C. Minussi, Michael D. Nicholson, Hanghui Ye, Alexander Davis, Kaile Wang, Toby Baker, Maxime Tarabichi, Emi Sei, Haowei Du, Mashiat Rabbani, Cheng Peng, Min Hu, Shanshan Bai, Yu-wei Lin, Aislyn Schalck, Asha Multani, Jin Ma, Thomas O. McDonald, Anna Casasent, Angelica Barrera, Hui Chen, Bora Lim, Banu Arun, Funda Meric-Bernstam, Peter Loo, Franziska Michor () and Nicholas E. Navin ()
Additional contact information
Darlan C. Minussi: The University of Texas MD Anderson Cancer Center
Michael D. Nicholson: Dana-Farber Cancer Institute
Hanghui Ye: The University of Texas MD Anderson Cancer Center
Alexander Davis: The University of Texas MD Anderson Cancer Center
Kaile Wang: The University of Texas MD Anderson Cancer Center
Toby Baker: The Francis Crick Institute
Maxime Tarabichi: The Francis Crick Institute
Emi Sei: The University of Texas MD Anderson Cancer Center
Haowei Du: The University of Texas MD Anderson Cancer Center
Mashiat Rabbani: The University of Texas MD Anderson Cancer Center
Cheng Peng: The University of Texas MD Anderson Cancer Center
Min Hu: The University of Texas MD Anderson Cancer Center
Shanshan Bai: The University of Texas MD Anderson Cancer Center
Yu-wei Lin: The University of Texas MD Anderson Cancer Center
Aislyn Schalck: The University of Texas MD Anderson Cancer Center
Asha Multani: The University of Texas MD Anderson Cancer Center
Jin Ma: The University of Texas MD Anderson Cancer Center
Thomas O. McDonald: Dana-Farber Cancer Institute
Anna Casasent: The University of Texas MD Anderson Cancer Center
Angelica Barrera: The University of Texas MD Anderson Cancer Center
Hui Chen: The University of Texas MD Anderson Cancer Center
Bora Lim: The University of Texas MD Anderson Cancer Center
Banu Arun: The University of Texas MD Anderson Cancer Center
Funda Meric-Bernstam: The University of Texas MD Anderson Cancer Center
Peter Loo: The Francis Crick Institute
Franziska Michor: Dana-Farber Cancer Institute
Nicholas E. Navin: The University of Texas MD Anderson Cancer Center

Nature, 2021, vol. 592, issue 7853, 302-308

Abstract: Abstract Our knowledge of copy number evolution during the expansion of primary breast tumours is limited1,2. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7–22) that are organized into a few (3–5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.

Date: 2021
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DOI: 10.1038/s41586-021-03357-x

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