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

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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.