Minussi, Darlan C.Nicholson, MichaelYe, HanghuiDavis, AlexanderWang, KaileBaker, TobyTarabichi, MaximeSei, EmiDu, HaoweiRabbani, MashiatPeng, ChengHu, MinBai, ShanshanLin, Yu-weiSchalck, AislynMultani, AshaMa, JinMcDonald, ThomasCasasent, AnnaBarrera, AngelicaChen, HuiLim, BoraArun, BanuMeric-Bernstam, FundaVan Loo, PeterMichor, FranziskaNavin, Nicholas E.2022-06-272021-03-24Minussi, Darlan C., Michael D. Nicholson, Hanghui Ye, Alexander Davis, Kaile Wang, Toby Baker, Maxime Tarabichi, et al. “Breast Tumours Maintain a Reservoir of Subclonal Diversity during Expansion.” Nature, March 24, 2021. https://doi.org/10.1038/s41586-021-03357-x.0028-08361476-4687https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37372409Our 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.en-USMultidisciplinaryJournal Article2022-06-2710.1038/s41586-021-03357-x