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.
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- Supplementary Text and Figures (7,903 KB)
Supplementary Figures 1–6, Supplementary Note
- Supplementary Source Code (12 KB)
R code for mutation clustering
- Supplementary Table 1 (147 KB)
Patient and sample characteristics
- Supplementary Table 2 (94 KB)
- Supplementary Table 3 (60 KB)
Annotation of potential driver genes
- Supplementary Table 4 (205 KB)
- Supplementary Table 5 (148 KB)
- Supplementary Table 6 (73 KB)
- Supplementary Table 7 (134 KB)
Mutation and copy number calls from capture data.
- Supplementary Table 8 (204 KB)
Coding mutations and oncogenic copy number events from whole genome data