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Journal Club
Secondary BRCA1 and BRCA2 alterations and acquired chemoresistance
Weixin Wang and William D. Figg
volume 7 | issue 7
July 2008Pages: 1004 - 1005
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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
Weixin Wang
Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland USA
William D. Figg
Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland USA