Person: Nicholson, Michael
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Publication Breast Tumours Maintain a Reservoir of Subclonal Diversity During Expansion
(Springer Science and Business Media LLC, 2021-03-24) Minussi, Darlan C.; Nicholson, Michael; Ye, Hanghui; Davis, Alexander; Wang, Kaile; Baker, Toby; Tarabichi, Maxime; Sei, Emi; Du, Haowei; Rabbani, Mashiat; Peng, Cheng; Hu, Min; Bai, Shanshan; Lin, Yu-wei; Schalck, Aislyn; Multani, Asha; Ma, Jin; McDonald, Thomas; Casasent, Anna; Barrera, Angelica; Chen, Hui; Lim, Bora; Arun, Banu; Meric-Bernstam, Funda; Van Loo, Peter; Michor, Franziska; Navin, Nicholas E.Our knowledge of copy number evolution during the expansion of primary breast tumors is limited. 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 triple-negative breast cancers (TNBCs) and 4 cell lines. Our data shows that breast tumors and cell lines are comprised of 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 LOH events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumor expansion. By subcloning single daughter cells in culture, we show that tumor cells re-diversify their genomes and do not retain isogenic properties. These data show that TNBCs continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumor growth.