BRCAREV: Unravelling how reversion mutations in the BRCA1 and BRCA2 tumour suppressor genes occur

癌症研究中的一个基本问题是什么决定了治疗的成功。目前，高达25%的乳腺癌患者（40-70%的预后不良三阴性亚型）和约5%的前列腺癌患者存在BRCA1/2缺乏症，适合用PARP抑制剂（PARPi）进行治疗。然而，由于耐药机制，超过40%的患者对这种治疗没有反应，而耐药机制尚未完全确定。我们建议通过研究肿瘤细胞如何对PARPi产生抗性来解决这个问题。在BRCAREV项目中，我们将结合计算机和“湿实验室”实验方法来分析这个问题，并使用在这项工作中获得的信息来生成一个预测器，以估计具有特定BRCA1或BRCA2突变的人是否会对PARPi产生耐药性的可能性。因此，这项工作将：(i)使BRCA1/BRCA2突变型癌症患者受益；（ii）建立一些基本规则，管理癌症相关突变如何引起耐药性；（iii）允许主小组（研究BRCA突变在癌症中的含义的先锋小组）和申请人（通过计算结构方法研究癌症基因组学的训练有素的研究人员）结合他们的知识，并产生一种新的BRCA突变癌症治疗方法，作为相互协同利益的跨学科项目的一部分，对研究人员和患者。

A fundamental question in cancer research is what determines the success of treatment. Currently, up to 25% of breast cancer patients (40-70% of the poor-prognosis Triple Negative subtype) and about 5% of prostate cancer patients have BRCA1/2 deficiency and are suitable for treatment with PARP inhibitors (PARPi). However, over 40% of these patients do not respond to this treatment due to resistance mechanisms, which are not fully characterised. We propose to address this question by studying how tumour cells become resistant to PARPi. In the BRCAREV project, we will combine in silico and "wet-lab" experimental approaches to dissect this problem and use the information gained in this work to generate a predictor that estimates the likelihood that a person with a particular BRCA1 or BRCA2 mutation will or will not develop resistance to PARPi. Therefore, this work will: (i) benefits patients with BRCA1/BRCA2 mutant cancers; (ii) establish some of the fundamental rules that govern how cancer-associated mutations cause drug resistance; (iii) allow both the host group (a pioneer group researching the implication of BRCA mutations in cancer) and the applicant (a highly trained researcher on cancer genomics through computational structural approaches) to combine their knowledge and to generate new one of BRCA-mutated cancer therapeutics as part of an interdisciplinary project of mutual synergistic benefit, to the researchers and patients.