Wu Xiaobing, Guo Maoni, Cui Jian, Cai Haoyang, Wang San Ming
MOE Frontiers Science Center for Precision Oncology, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China.
Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, NE, USA.
Oncogenesis. 2022 Jul 22;11(1):41. doi: 10.1038/s41389-022-00417-3.
BRCA1 mutation is the genetic predisposition in causing genome instability towards cancer. BRCA1 mutation is predominantly germline inherited at the fertilization. However, when the inherited mutation initiates genome instability in the mutation carriers remains largely elusive. We used a heterozygotic Brca1-knockout mouse as a model to investigate the issue. Through whole-genome sequencing and bioinformatics analysis, we monitored genome status across the developmental stages from embryo to adulthood in the mouse model. We observed that genome instability as reflected by structural variation, indel and copy number variation already appeared at 10.5-day embryo and progressively towards adulthood. We also observed that the genome instability was not linearly accumulated but dynamically changed along the developmental process, affecting many oncogenic genes and pathways including DNA damage repair, estrogen signaling, and oncogenesis. We further observed that many genome abnormalities in the cancer caused by Brca1 mutation were originated at embryonic stage, and Trp53 (TP53) mutation was not essential for the Brca1 mutation-caused genome instability in the non-cancer cells. Our study revealed that heterozygotic Brca1 mutation alone can cause genome instability at embryonic stage, highlighting that prevention of BRCA1 mutation-related cancer in humans may need to start earlier than currently considered.
BRCA1突变是导致基因组不稳定进而引发癌症的遗传易感性因素。BRCA1突变主要在受精时通过种系遗传。然而，遗传突变在突变携带者中引发基因组不稳定的机制在很大程度上仍不清楚。我们使用杂合性Brca1基因敲除小鼠作为模型来研究这个问题。通过全基因组测序和生物信息学分析，我们监测了该小鼠模型从胚胎到成年各个发育阶段的基因组状态。我们观察到，由结构变异、插入缺失和拷贝数变异所反映的基因组不稳定在胚胎10.5天时就已出现，并在发育至成年的过程中逐渐加剧。我们还观察到，基因组不稳定并非呈线性累积，而是在发育过程中动态变化，影响了许多致癌基因和信号通路，包括DNA损伤修复、雌激素信号传导和肿瘤发生。我们进一步观察到，由Brca1突变导致的癌症中的许多基因组异常都起源于胚胎期，并且Trp53（TP53）突变对于非癌细胞中Brca1突变引起的基因组不稳定并非必不可少。我们的研究表明，单纯的杂合性Brca1突变就能在胚胎期导致基因组不稳定，这突出表明预防人类BRCA1突变相关癌症可能需要比目前认为的更早开始。
