Identification of novel breast cancer susceptibility genes through exome sequencing: a population-specific approach based on Slavic founder mutations

我们的研究项目旨在确定乳腺癌的新的遗传风险因素，并探索它们相关的风险贡献。以前的证据表明，这种研究在具有创始人效应的种族同质人群中比在混合人群中更有效，尤其是东斯拉夫人。拟议的项目将来自俄罗斯和白俄罗斯学术机构的患者与申请人在汉诺威医学院的S机构的患者结合在一起。参与机构已经合作多年，患者样本和临床或流行病学数据已经准备就绪。该项目为期两年，包括三个连续的阶段，每个阶段6-9个月：1.对来自俄罗斯和白俄罗斯的遗传性乳腺癌患者的假名样本进行外显子组测序(n=200)。候选乳腺癌易感基因中新的或非常罕见的功能相关变异将使用桑格测序进行验证。其中96人将进入下一阶段。优先候选创始人突变将在俄罗斯和白俄罗斯乳腺癌患者和对照中进行更大规模的基因分型(DFG项目中每组n=2,500，加上平行RFBR项目中的另外2,000个病例/2,000个对照)，以测试它们与乳腺癌的关联，并在分层分析中定义它们的风险估计。从阶段1和阶段2中选出的最强的24个候选基因将通过在MHH的一个德国病例对照系列(n=1,000个病例/1,000个对照)中对它们的整个编码区进行高度平行的扩增序列来进一步测试它们在乳腺癌中的作用。预计这个项目的结果将指导识别新的乳腺癌风险因素，然后可以在功能、药理学和临床水平上表征这些因素。申请者是领先的国际乳腺癌联盟的活跃成员，这些数据将在联合调查研究中进一步利用。

Our research project aims to identify novel genetic risk factors for breast cancer and to explore their associated risk contribution. Previous evidence has shown that such research is more effective in ethnically homogenous populations with founder effects, specifically the East Slavs, than in mixed populations. The proposed project combines patients from Russian and Byelorussian academic institutions with those from the applicant´s institution at Hannover Medical School. The participating institutions are collaborating for many years, patient samples and clinical or epidemiological data are already at hand. With a total duration of two years, this project comprises three consecutive phases of 6-9 months each: 1. Pseudonymised samples from Russian and Byelorussian patients with hereditary breast cancer will be investigated through exome sequencing (n= 200 patients). Novel or very rare functionally relevant variants in candidate breast-cancer susceptibility genes will be validated using Sanger sequencing. 96 of them will be put to the next stage.2. The prioritised candidate founder mutations will be genotyped at a larger scale in Russian and Byelorussian breast cancer patients and controls (n=2,500 for each group in this DFG project plus another 2,000 cases/ 2,000 controls in the parallel RFBR project) to test for their association with breast cancer and define their risk estimates in stratified analyses.3. The strongest 24 candidate genes selected from stage 1 and stage 2 will be further tested for their role in breast cancer by means of highly parallel amplicon sequencing of their whole coding region in a German case-control series at MHH (n= 1,000 cases/1,000 controls).It is expected that the results of this project will guide the identification of novel risk factors for breast cancer which can then be characterised at the functional, pharmacological and clinical level. The applicants are active members in leading international breast cancer consortia where the data will be exploited further in joint investigational studies.