Evolutionary histories of breast cancer and related clones

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development(1-3). However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.

Automated summary

Recent studies have shown that clones carrying common cancer mutations frequently evolve in normal tissues, but we still lack knowledge about the additional driver events that occur before these clones evolve into cancer. In this study, using phylogenetic analyses, we found unique evolutionary histories in breast cancers with der(1;16), a common driver alteration. The timing of early evolutionary events was estimated and showed that both cancer and non-cancer clones evolved from a common ancestor in the patient's early 30s. Multiple independent cancer founders from non-cancer ancestors were also observed, contributing to intratumor heterogeneity. These findings provide new insights into the evolution of breast cancer.