title: Punctuated copy number evolution and clonal stasis in triple-negative breast cancer.
abstract: Aneuploidy is a hallmark of breast cancer; however, knowledge of how these complex genomic rearrangements evolve during tumorigenesis is limited. In this study, we developed a highly multiplexed single-nucleus sequencing method to investigate copy number evolution in patients with triple-negative breast cancer. We sequenced 1,000 single cells from tumors in 12 patients and identified 1-3 major clonal subpopulations in each tumor that shared a common evolutionary lineage. For each tumor, we also identified a minor subpopulation of non-clonal cells that were classified as metastable, pseudodiploid or chromazemic. Phylogenetic analysis and mathematical modeling suggest that these data are unlikely to be explained by the gradual accumulation of copy number events over time. In contrast, our data challenge the paradigm of gradual evolution, showing that the majority of copy number aberrations are acquired at the earliest stages of tumor evolution, in short punctuated bursts, followed by stable clonal expansions that form the tumor mass.
authors.affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ruli
authors.initials: R
authors.lastname: Gao
authors.affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Davis
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: McDonald
authors.affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Emi
authors.initials: E
authors.lastname: Sei
authors.affiliation: Peking Union Medical College, Department of Medical Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Pei-Ching
authors.initials: PC
authors.lastname: Tsai
authors.affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Casasent
authors.affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Waters
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
authors.affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Navin
mesh_terms: D018270:Carcinoma, Ductal, Breast / Q000235:genetics*; D002999:Clone Cells; D004273:DNA, Neoplasm; D005260:Female; D018628:Gene Dosage; D018740:Genetic Heterogeneity; D006801:Humans; D017422:Sequence Analysis, DNA; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm