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McDonald, Thomas

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McDonald

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McDonald, Thomas

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2016 - 201912020 - 20211

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Author's Publications: search.filters.isAuthorOfPublication.29ab1970-3805-4f98-9e61-76a0fb623c1f

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    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.
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    Punctuated copy number evolution and clonal stasis in triple-negative breast cancer
    (Springer Nature, 2016) Gao, Ruli; Davis, Alexander; McDonald, Thomas; Sei, Emi; Shi, Xiuqing; Wang, Yong; Tsai, Pei-Ching; Casasent, Anna; Waters, Jill; Zhang, Hong; Meric-Bernstam, Funda; Michor, Franziska; Navin, Nicholas E.
    Aneuploidy is a hallmark of breast cancer; however, our knowledge of how these complex rearrangements evolve during tumorigenesis is limited. In this study we developed a highly-multiplexed single-nucleus-sequencing (HM-SNS) method to investigate DNA copy number evolution in triple-negative breast cancer (TNBC) patients. We applied this method to sequence 1000 single cells from 12 TNBC patients and identified 1-3 major clonal subpopulations in each tumor, with large genetic distances from the ancestral diploid cells. Mathematical modeling suggests that these data are unlikely to be explained by the gradual accumulation of copy number aberrations (CNAs) over extended periods of time. We also identified a minor (~7%) subpopulation of non-clonal cells that were classified as: 1) metastable tumor cells, 2) pseudo-diploid cells, and 3) chromazemic cells. Collectively, these data challenge the paradigm of gradual copy number evolution by showing that the majority of CNAs are acquired early in tumor evolution, in short punctuated bursts, followed by stable clonal expansions that form the tumor mass. These data have important implications for understanding the evolutionary dynamics of tumor growth and the diagnosis and treatment of TNBC patients.