Whole-genome Analysis Informs Breast Cancer Response to Aromatase Inhibition

Nature. 2012 Jun 10;486(7403):353-60. doi: 10.1038/nature11143.

Abstract

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.

Publication types

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

MeSH terms

  • Anastrozole
  • Androstadienes / pharmacology
  • Androstadienes / therapeutic use
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Aromatase / metabolism*
  • Aromatase Inhibitors / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • DNA Repair
  • Exome / genetics
  • Exons / genetics
  • Female
  • Genetic Variation / genetics
  • Genome, Human / genetics*
  • Humans
  • Letrozole
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase Kinase 1 / genetics
  • Mutation / genetics
  • Nitriles / pharmacology
  • Nitriles / therapeutic use
  • Receptors, Estrogen / metabolism
  • Treatment Outcome
  • Triazoles / pharmacology
  • Triazoles / therapeutic use

Substances

  • Androstadienes
  • Antineoplastic Agents
  • Aromatase Inhibitors
  • Nitriles
  • Receptors, Estrogen
  • Triazoles
  • Anastrozole
  • Letrozole
  • Aromatase
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human
  • exemestane

Associated data

  • GEO/GSE29442
  • GEO/GSE35191