Yates, Lucy RGerstung, MoritzKnappskog, StianDesmedt, ChristineGundem, GunesLoo, Peter VanAas, TuridAlexandrov, Ludmil BLarsimont, DenisDavies, HelenLi, YilongJu, Young SeokRamakrishna, ManasaHaugland, Hans KristianLilleng, Peer KaareNik-Zainal, SerenaMcLaren, StuartButler, AdamMartin, SanchaGlodzik, DominicMenzies, AndrewRaine, KeiranHinton, JonathanJones, DavidMudie, Laura JJiang, BingVincent, DelphineGreene-Colozzi, AprilAdnet, Pierre-YvesFatima, AquilaMaetens, MarionIgnatiadis, MichailStratton, Michael RSotiriou, ChristosRichardson, Andrea LLønning, Per EysteinWedge, David CCampbell, Peter J2016-02-012015Yates, L. R., M. Gerstung, S. Knappskog, C. Desmedt, G. Gundem, P. V. Loo, T. Aas, et al. 2015. “Subclonal diversification of primary breast cancer revealed by multiregion sequencing.” Nature medicine 21 (7): 751-759. doi:10.1038/nm.3886. http://dx.doi.org/10.1038/nm.3886.1078-8956http://nrs.harvard.edu/urn-3:HUL.InstRepos:24983947Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient’s tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole genome and targeted sequencing to multiple samples from each of 50 patients’ tumors (total 303). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13/50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resisting chemotherapy and acquiring invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.en-USJournal Article2016-02-0110.1038/nm.3886