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New York [US],: Researchers from Weill Cornell Medicine have discovered that individuals who inherit a faulty copy of the BRCA1 gene may develop mutations and cancer due to error-prone DNA replication and repair.
The finding might have an impact on how patients with these mutations can avoid getting cancer.
“We have identified some of the first steps in cancer development in people carrying inherited BRCA1 mutations,” said the study’s senior author Dr. Jeannine Gerhardt, assistant professor of stem cell biology in obstetrics and gynecology and the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Weill Cornell Medicine.
To understand why the remaining functional BRCA1 gene copy often becomes mutated too, the team studied the DNA replication in human embryonic stem cells as well as human breast epithelial cells with one mutant copy of the BRCA1 gene. The human embryonic stem cells were generated in the Center for Reproductive Medicine by Dr. Nikica Zaninovic and Dr. Zev Rosenwaks. They exposed the cells to a chemical to mimic environmental stress on the cells. They discovered that as the DNA in these cells unzips into two strands to make a copy of the DNA for each new cell, the machinery that copies the DNA stalls at the BRCA1 gene because of the gene’s repetitive DNA sequences.
The team also demonstrated for what is believed to be the first time that the BRCA genes are fragile sites and are prone to breakage. Because the cells only have half as much of the BRCA1 protein available to repair the breaks, the cells turn to a more error-prone backup DNA repair mechanism called microhomology-mediated break-induced replication (MMBIR), Dr. Deshpande explained.
The team also examined tumor cells from women with breast cancer linked to inherited BRCA1 mutations. They found mutations in the BRCA1 and BRCA2 genes, like deletions and insertions, likely caused by the faulty MMBIR process.
The team is also working to develop strategies to prevent the use of error-prone DNA repair mechanisms in women with inherited BRCA1 mutations. For example, they are testing the protective effects of dietary compounds that are linked to reduced breast cancer risk in BRCA1 mutation carriers. If they are successful, they may be able to identify drugs or other interventions that could prevent cancer in women with inherited BRCA1 mutations and provide an alternative to the existing invasive preventive measures like pre-emptive mastectomy or ovary removal.
