Punctuated copy number evolution and clonal stasis in triple-negative breast cancer

Abstract

Aneuploidy is a hallmark of breast cancer; however, our 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 triple-negative breast cancer patients. We sequenced 1000 single cells from 12 patients and identified 1–3 major clonal subpopulations in each tumor that shared a common evolutionary lineage. We also identified a minor subpopulation of non-clonal cells that were classified as: 1) metastable, 2) pseudo-diploid, or 3) 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.

The evolution of tumour phylogenetics: principles and practice

“…We then imagine that we built a phylogeny using an off-the-shelf neighbour joining phylogeny program 152 , as was done in several prominent studies 71,76,80,97,145,158 . This is a qualitatively similar plan to the pioneering work of Navin et al 71,157 . How can we evaluate, and perhaps improve upon, this initial plan?…”

“…Navin et al 71 relied on neighbour joining 155 , which had earlier been used by Frumkin et al 76 with microsatellite data, to infer phylogenies from scSeq-derived CNVs. Neighbour joining was also used by Xu et al 80 for application to renal cancers and by Wang et al 156 for what was, until recently 157 , the largest scSeq study of tumour evolution.…”

Clonal selection and asymmetric distribution of human leukemia in murine xenografts revealed by cellular barcoding

“…6 However, with the progress of sequencing technology and collection of massive amounts of data, a more complex picture of cancer clonal composition has emerged. 7,8 Insight into clonal heterogeneity of leukemia and its evolution is of utmost importance because it may fuel emergence of novel, clinically relevant biological features, such as more aggressive growth or drug resistance. 9 However, especially in acute lymphoblastic leukemia (ALL), many aspects of clonal evolution are subject to ongoing debate.…”

Cancer evolution and heterogeneity

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This multiregional analysis (MRA) sequencing approach enabled us not only to observe spatial heterogeneity, but also to calculate temporal alterations and eventually disclose the evolution of tumors. There are two types of somatic aberration in a tumor: ubiquitous aberrations (founder mutations, trunk mutations, or clonal mutations) and scattered aberrations (progressor mutations, branch/leaf mutations, or subclonal mutations).…”