Brca2 deficiency drives gastrointestinal tumor formation and is selectively inhibited by mitomycin C

Xiaomin Chen,Xiaomin Chen,Yan Ji,Yan Ji,Honggang Xiang,Fangfei Peng,Fangfei Peng,Yongfeng Zhang,Yongfeng Zhang,Yumin Han,Yumin Han,Tingting Liu,Tingting Liu,Heng Wang,Heng Wang,Xiang Wang,Xiang Wang,Xiangyin Kong,Xiangyin Kong,Jing-Yu Lang,Jing-Yu Lang,Changxu Wang,Changxu Wang

doi:10.1038/s41419-020-03013-8

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.

Highlights

Homologous recombination (HR) is an evolutionarily conserved process for repairing DNA double-strand breaks (DSBs) with high fidelity[1]
BRCA2 is frequently mutated in both gastric and colorectal tumor samples and is associated with microsatellite instability By retrieving the TCGA stomach cancer database[28,31,32], we observed that genes belonging to the Fanconi anaemia (FA) pathway were frequently mutated in gastric adenocarcinoma[33,34,35] (Fig. 1a)
(see figure on previous page) Fig. 2 MMC induces DSBs and shows potent killing effects in BRCA2 monoallelic and biallelic mutant tumor cells. a After SNU-1, SNU-5 and HGC-27 cells were treated with the indicated drugs for 72 h, the cell viability was determined at OD570, with normalization to DMSO treatment. b Representative images of γ-H2AX and BRCA2 foci formation in BRCA2 wild-type and mutant cell lines after treated with 0.3 μM MMC for 18 h

Summary

Introduction

Homologous recombination (HR) is an evolutionarily conserved process for repairing DNA double-strand breaks (DSBs) with high fidelity[1]. Upon DNA damage, HR-repair proteins such as BRCA2 directly bind with RAD51 through BRC motifs and promote RAD51 filament formation to recruit homologous templates to complete error-free DSB repair[2,3,4]. With no requirement for homologous template is an alternative process used to repair DSBs with potential genome instability, which accelerates tumor development[6,7]. BRCA2 is mutated in approximately 2.5% of breast cancers and 6% of ovarian cancers[10,11]. The inappropriate DSB repair caused by defective BRCA1/2 often leads to chromosomal dislocation, this is not sufficient to drive tumor formation per se.

Methods

Results

Conclusion