Secondary BRCA1 and BRCA2 alterations and acquired chemoresistance

Cancer Biol Ther. 2008 Jul;7(7):1004-5. doi: 10.4161/cbt.7.7.6409.


Tumor suppressor BRCA1 and BRCA2 are frequently mutated in familial breast and ovarian cancer. More than ten percent of women with breast or ovarian cancer carry BRCA1 or BRCA2 (BRCA1/2) mutations. Cancers that arise in mutation carriers have often lost the wild-type allele through somatic alterations during tumor progression. BRCA1/2 play important roles in homologous recombination repair of DNA double-strand breaks. Because of this, BRCA1/2-deficient cancers often have a better response to DNA cross-linking agents such as platinum analogues and to poly(ADP-ribose) polymerase (PARP) inhibitors. However, over time, the majority of these BRCA1/2-deficient cancers become resistant and patients die from refractory diseases. Three recent studies demonstrated that acquired resistance to platinum analogues or PARP inhibitors in tumors carrying frame-shift BRCA1/2 mutations came from restored BRCA1/2 expression and HR function due to secondary intragenic mutations that corrected the open reading frames of mutated BRCA1/2.

Publication types

  • Review

MeSH terms

  • Alleles
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / physiology*
  • BRCA2 Protein / genetics*
  • BRCA2 Protein / physiology*
  • Breast Neoplasms / genetics
  • Cisplatin / pharmacology
  • DNA Repair
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Mutation*
  • Ovarian Neoplasms / genetics
  • Protein Isoforms


  • BRCA1 Protein
  • BRCA2 Protein
  • Protein Isoforms
  • Cisplatin