Anna Khalizieva1,2,3, Sarah C. Moser1,2, Peter Bouwman3 and Jos Jonkers1,2 1Division of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; 2Oncode Institute, 3521 AL Utrecht, The Netherlands; 3Division of Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands Corresponding authors: j.jonkersnki.nl, s.mosernki.nl, r.j.p.bouwmanlacdr.leidenuniv.nl Abstract

The discovery of BRCA1 and BRCA2 as tumor susceptibility genes and their role in genome maintenance has transformed our understanding of hereditary breast and ovarian cancer. This review traces the evolution of BRCA1/2 research over the past 30 years, highlighting key discoveries in the field and their contributions to tumor development. Additionally, we discuss current preventive measures for BRCA1/2 mutation carriers and targeted treatment options based on the concept of synthetic lethality. Finally, we explore the challenges of acquired therapy resistance and discuss potential alternative avenues for targeting BRCA1/2 mutant tumors.