Genomic instability in breast cancer: pathogenesis and clinical implications

Mol Oncol. 2010 Jun;4(3):255-66. doi: 10.1016/j.molonc.2010.04.001. Epub 2010 Apr 9.

Abstract

Breast cancer is a heterogeneous disease, appreciable by molecular markers, gene-expression profiles, and most recently, patterns of genomic alteration. In particular, genomic profiling has revealed three distinct patterns of DNA copy-number alteration: a "simple" type with few gains or losses of whole chromosome arms, an "amplifier" type with focal high-level DNA amplifications, and a "complex" type marked by numerous low-amplitude changes and copy-number transitions. The three patterns are associated with distinct gene-expression subtypes, and preferentially target different loci in the genome (implicating distinct cancer genes). Moreover, the different patterns of alteration imply distinct underlying mechanisms of genomic instability. The amplifier pattern may arise from transient telomere dysfunction, although new data suggest ongoing "amplifier" instability. The complex pattern shows similarity to breast cancers with germline BRCA1 mutation, which also exhibit "basal-like" expression profiles and complex-pattern genomes, implicating a possible defect in BRCA1-associated repair of DNA double-strand breaks. As such, targeting presumptive DNA repair defects represents a promising area of clinical investigation. Future studies should clarify the pathogenesis of breast cancers with amplifier and complex-pattern genomes, and will likely identify new therapeutic opportunities.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / genetics*
  • Chromosome Aberrations
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genomic Instability*
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Phenotype

Substances

  • BRCA1 Protein
  • Biomarkers, Tumor
  • DNA, Neoplasm