Abstract 2371: Multi-cell phylogenetic inference of copy number evolution in breast cancer

Aneuploidy is a hallmark of breast cancer, but little is known about how these complex genomic rearrangements evolve during tumor growth. To investigate this question, we developed a Highly-Multiplexed Single Nucleus Sequencing (HM-SMS) method to profile genome-wide copy number in individual tumor cells and compared multiple cells to infer evolutionary lineages. We applied this method to analyze thousands of single cells from 12 triple-negative breast cancer patients and 10 ductal-carcinoma-in-situ (DCIS) patients. Integer copy number profiles were calculated from a combination of sequencing data and ploidy estimation using flow cytometry. A multi-cell segmentation algorithm was used to identify common CNA events that are shared between tumor cells in each patient. Trinary event matrices were calculated for each patient to determine the presence or absence of individual copy number aberrations (CNAs) in individual cells. Using the maximum parsimony criterion, we inferred a phylogenetic tree for each tumor and estimated the temporal order of the CNAs.. Our data suggest that most tumors consisted of 1-4 major clonal subpopulations that shared a common evolutionary lineage, suggesting that they evolved from a single normal cell in the breast tissue. Furthermore our data support a punctuated model of copy number evolution, which which the majority of CNAs were acquired in a short evolutionary burst, followed by one or more stable clonal expansions to form the tumor mass. Citation Format: Alexander J. Davis, Ruli Gao, Emi Sei, Pei-Ching Tsai, Anna Casasent, Amy Zhang, Xiuqing Shi, Yong Wang, Jill Waters, Funda Meric-Bernstam, Mary Edgerton, Nicholas Navin. Multi-cell phylogenetic inference of copy number evolution in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2371.