Impact of regulatory variants in genes predisposing for hereditary breast and ovarian cancer

• Applicant: Professorin Dr. Doris Steinemann
• Subject Area: Human Genetics
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458888638

BRCA1 and BRCA2 are involved in the maintenance of genomic stability via homologous recombination ensuring the precise repair of DNA double-strand breaks. Pathogenic loss-of-function variants (PVs) in the highly penetrant BRCA1 and BRCA2 genes increase the risk of developing breast and/or ovarian cancer (HBOC) dramatically. However, about 50% of hereditary risk for HBOC remains unexplained after state of the art diagnostic procedures. Since intronic regions have been neglegted we hypothesize that aberrant splicing events lead to a loss of BRCA1/2 function and could explain the missing hereditary for HBOC predisposition. We will perform whole genome sequencing (WGS) in a selected diagnosis-negative patient cohort to identify deep intronic pathogenic variants which may lead to alternative splicing and in turn loss of function. First, we aim to characterize new deep intronic variants in silico using appropriate bioinformatic tools. Patients carrying a variant with high predictive scores regarding splicing and expression will be analyzed for tumor mutational signatures indicative of homologous recombination deficiency. In parallel whole transcriptome sequencing (WTS) will be performed using patient-derived LCLs and/or tumor tissue from this selected patient cohort in order to prove alternative transcripts and/or transcript levels. Functional consequences of putative splice-variants will be characterized in vitro by means of minigene assays. Using WGS and WTS technology we aim to identify more patients at risk for developing breast and/or ovarian cancer due to regulatory variants in the BRCA1/2 genes. The identification and classification of new candidate variants into pathogenic loss of function variants will offer targeted therapeutic options and prevention of BRCA-related cancers.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Monika Mariola Golas