A team led by the Jackson Laboratory’s (JAX) Professor Edison Liu, M.D., and Research Scientist Francesca Menghi, Ph.D., used patient data, patient-derived xenograft (PDX) mouse models, and engineered cancer cell lines to investigate why people with BRCA mutations respond better and are less likely to develop platinum-based therapy resistance than patients with BRCA1 promoter methylation.
Many breast and ovarian cancers arise in people with mutations in BRCA1 or BRCA2, two genes involved in DNA repair. In other patients, however, the genes are not mutated, but instead BRCA1 is suppressed by the addition of a chemical compound, a process called methylation, at the DNA sequence that regulates its expression. BRCA1 and BRCA2 mutations are much more sensitive to chemotherapeutic agents, and treatment can result in complete remissions and even cures. Strangely, however, while mutations and methylation both promote cancer initiation through the loss of functional BRCA1 and/or BRCA2 proteins, patients respond differently to a standard therapy (including platinum-based chemotherapy agents, such as carboplatin) depending on whether they have a mutated BRCA gene or methylated BRCA1.
It was not previously understood why those with BRCA mutations respond better and are less likely to develop platinum-based therapy resistance than patients with BRCA1 promoter methylation. A team led by Jackson Laboratory (JAX) Professor Edison Liu, M.D., and Research Scientist Francesca Menghi, Ph.D., used patient data, patient-derived xenograft (PDX) mouse models, and engineered cancer cell lines to investigate the difference. In “Genomic and epigenomic BRCA alterations predict adaptive resistance and response to platinum-based therapy in patients with triple-negative breast and ovarian carcinomas,” a paper published in Science Translational Medicine, they reveal the molecular basis of this difference in response.
Read the full story on The Jackson Laboratory website here.