1. Molecular Oncology,
2. Centre for Translational and Applied Genomics,
3. Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver V5Z 1L3, Canada
4. Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver V5Z 1L3, Canada
5. Department of Pathology, University of British Columbia, G227-2211 Wesbrook Mall, British Columbia, Vancouver V6T 2B5, Canada
6. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
7. Deeley Research Centre, BC Cancer Agency, Victoria V8R 6V5, Canada
8. These authors contributed equally to this work.

Correspondence to: Marco A. Marra³Samuel Aparicio^1,2,5 Correspondence and requests for materials should be addressed to M.A.M. (Email: mmarra@bcgsc.ca) or S.A. (Email: saparicio@bccrc.ca).

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Recent advances in next generation sequencing^{1, 2, 3, 4} have made it possible to precisely characterize all somatic coding mutations that occur during the development and progression of individual cancers. Here we used these approaches to sequence the genomes (>43-fold coverage) and transcriptomes of an oestrogen-receptor--positive metastatic lobular breast cancer at depth. We found 32 somatic non-synonymous coding mutations present in the metastasis, and measured the frequency of these somatic mutations in DNA from the primary tumour of the same patient, which arose 9 years earlier. Five of the 32 mutations (in ABCB11, HAUS3, SLC24A4, SNX4 and PALB2) were prevalent in the DNA of the primary tumour removed at diagnosis 9 years earlier, six (in KIF1C, USP28, MYH8, MORC1, KIAA1468 and RNASEH2A) were present at lower frequencies (1–13%), 19 were not detected in the primary tumour, and two were undetermined. The combined analysis of genome and transcriptome data revealed two new RNA-editing events that recode the amino acid sequence of SRP9 and COG3. Taken together, our data show that single nucleotide mutational heterogeneity can be a property of low or intermediate grade primary breast cancers and that significant evolution can occur with disease progression.

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