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The sequencing of 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 (303 samples in total). 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 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of 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.

Original publication

DOI

10.1038/nm.3886

Type

Journal article

Journal

Nat Med

Publication Date

07/2015

Volume

21

Pages

751 - 759

Keywords

Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Breast Neoplasms, Cell Proliferation, Clone Cells, Cohort Studies, DNA Copy Number Variations, Female, Genetic Variation, Genomics, High-Throughput Nucleotide Sequencing, Humans, Middle Aged, Mutation