Evolutionary histories of breast cancer and related clones - Article

Sep 24, 2026

Uploaded by Fahsai

Recent studies report frequent evolution of clones carrying shared cancer mutations in seemingly normal tissues, but they leave unanswered the sequence and timing of additional driver events before cancer emerges. Using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, the study reconstructs distinct evolutionary histories of breast cancers with der(1;16) and estimates early timing from mutation rates in normal epithelial cells.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages30

Reading Time1 h 16 min

AccessFree to download

Evolutionary histories of breast cancer and related clones

Study approach and data sources

Findings on der(1;16) acquisition and clonal expansion

Implications for timing and driver events

Comparison with additional case patterns

Article | Evolutionary histories of breast cancer and related clones | | | | --- | --- | --- | | [https://doi.org/10.1038/s41586-023-06333-9](https://doi.org/10.1038/s41586-023-06333-9) | Tomomi Nishimura1,2,3,26, Nobuyuki Kakiuchi1,4,5,26, Kenichi Yoshida1,6, Takaki Sakurai7,8, Tatsuki R. Kataoka7,9, Eiji Kondoh10,11, Yoshitsugu Chigusa10, Masahiko Kawai12,
Morio Sawada13, Takuya Inoue13, Yasuhide Takeuchi1,7, Hirona Maeda1,7, Satoko Baba14,15,16, Yusuke Shiozawa1, Ryunosuke Saiki1, Masahiro M. Nakagawa1,2, Yasuhito Nannya1,17, Yotaro Ochi1, Tomonori Hirano1,5,18, Tomoe Nakagawa1,18, Yukiko Inagaki-Kawata1,3, Kosuke Aoki1, Masahiro Hirata7, Kosaku Nanki19, Mami Matano19, Megumu Saito19,20,
Eiji Suzuki3,21, Masahiro Takada3, Masahiro Kawashima3, Kosuke Kawaguchi3, Kenichi Chiba22, Yuichi Shiraishi22, Junko Takita12, Satoru Miyano23,24, Masaki Mandai10, Toshiro Sato19, Kengo Takeuchi14,15,16, Hironori Haga7, Masakazu Toi3,27 & Seishi Ogawa1,18,25,27✉
Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1–3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clonesin 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), acommon 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 thenon-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironmentsand/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from anAKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves. | | | Received: 4 July 2022 | | | | Accepted: 15 June 2023 | | | | Published online: 26 July 2023 | | | | Open access | | | | Check for updates | | | | Revolutionized sequencing technologies have enabled a series of | | frequently obscure the order of early driver events that are often | | recent studies on clones evolving in apparently normal tissues, which | | assigned together to a long major trunk in the phylogenetic tree9–11. | | are documented by sensitively detecting clone-defining somatic muta- | | Moreover, they do not help map the timing at which cancer clones | | tions1–7. In view of cancer development, a key observation through | | emerged or track the fate of other related non-cancer clones. To answer | | these studies is that clonal outgrowth in normal or non-cancer tissues | | these issues, analyses of both cancer and non-cancer lesions areabso- | | is common, often pervasive and frequently driven by common cancer | | lutely needed, although these are frequently hampered by the fact that | | mutations1. This immediately points to an important implication to | | atthe time of cancer diagnosis or surgery, genetically related non-cancer | | the early history of cancer that one or more of those positively selected | | clones are probably swept out by rapidly expanded cancer clones8,12,13. | | non-cancer clones should be destined for subsequent cancer devel-

FAQs

What is the main gap in knowledge addressed about breast cancer evolution?

The document highlights uncertainty about what additional driver events occur, in what order, and how related non-cancer clones progress before cancer develops.

How did the researchers infer evolutionary histories in this study?

They used phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions.

What did the study show about cancers with der(1;16)?

In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by emergence of a common ancestor by the patient’s early 30s, with subsequent evolution of both cancer and non-cancer clones.

Sep 24, 2026

Uploaded by Fahsai