Jos Jonkers

Thirty Years of BRCA1: Mechanistic Insights and Their Impact on Mutation Carriers

Abstract Thirty years ago, the cloning of the first breast cancer susceptibility gene, BRCA1, marked a milestone in our understanding of hereditary breast and ovarian cancers. This discovery initiated extensive research into DNA repair mechanisms, BRCA1-associated tumorigenesis, and therapeutic interventions. Despite these advances, critical questions remain unanswered, such as the evolution of BRCA1-associated tumors and their tissue specificity. These issues hinder the development of effective treatment and prevention strategies, which ultimately aim to improve the quality of life for BRCA1 mutation carriers. In this review, we discuss current knowledge, identify existing gaps, and suggest possible avenues to tackle these challenges. Significance: Here, we explore the impact of three decades of BRCA1 research on the lives of mutation carriers and propose strategies to improve the prevention and treatment of BRCA1-associated cancer.

Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors

BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.