title: Secondary BRCA1 and BRCA2 alterations and acquired chemoresistance.
abstract: 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.
authors: Medical Oncology Branch, National Cancer Institute; Bethesda, Maryland 20892, USA.
authors: Weixin
authors: W
authors: Wang
authors: William D
authors: WD
authors: Figg
mesh_terms: D000483:Alleles; D019313:BRCA1 Protein / Q000235:genetics* / Q000502:physiology*; D024682:BRCA2 Protein / Q000235:genetics* / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics; D020033:Protein Isoforms
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D020033:Protein Isoforms; D002945:Cisplatin