Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution

Nature. 2009 Oct 8;461(7265):809-13. doi: 10.1038/nature08489.


Recent advances in next generation sequencing 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-alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • DNA Mutational Analysis
  • Disease Progression
  • Estrogen Receptor alpha / metabolism
  • Evolution, Molecular
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, Neoplasm / genetics*
  • Genome, Human / genetics
  • Germ-Line Mutation / genetics
  • Humans
  • Mutagenesis / genetics*
  • Mutation / genetics*
  • Neoplasm Metastasis
  • Nucleotides / genetics*
  • RNA Editing / genetics
  • Signal Recognition Particle / genetics
  • Time Factors


  • Adaptor Proteins, Vesicular Transport
  • COG3 protein, human
  • Estrogen Receptor alpha
  • Nucleotides
  • SRP9 protein, human
  • Signal Recognition Particle