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Abstract
BRCA2 is crucial for repairing DNA double-strand breaks with high fidelity, and loss of BRCA2 increases the risks of developing breast and ovarian cancers. Herein, we show that BRCA2 is inactively mutated in 10% of gastric and 7% of colorectal adenocarcinomas, and that this inactivation is significantly correlated with microsatellite instability. Villin-driven Brca2 depletion promotes mouse gastrointestinal tumor formation when genome instability is increased. Whole-genome screening data showed that these BRCA2 monoallelic and biallelic mutant tumors were selectively inhibited by mitomycin C. Mechanistically, mitomycin C provoked double-strand breaks in cancer cells that often recruit wild-type BRCA2 for repair; the failure to repair double-strand breaks caused cell-cycle arrest at the S phase and p53-mediated cell apoptosis of BRCA2 monoallelic and biallelic mutant tumor cells. Our study unveils the role of BRCA2 loss in the development of gastrointestinal tumors and provides a potential therapeutic strategy to eliminate BRCA2 monoallelic and biallelic mutant tumors through mitomycin C.
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Details

1 Chinese Academy of Sciences, CAS_Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309)
2 Chinese Academy of Sciences, Bioinformatics Core, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309)
3 Pudong New Area People’s Hospital affiliated to Shanghai University of Medicine & Health Science, Department of General Surgery, Shanghai, China (GRID:grid.507037.6)