The molecular events and transcriptional plasticity driving brain metastasis in clinically relevant breast tumor subtypes has not been determined. Here we comprehensively dissect genomic, transcriptomic and clinical data in patient-matched longitudinal tumor samples, and unravel distinct transcriptional programs enriched in brain metastasis. We report on subtype specific hub genes and functional processes, central to disease-affected networks in brain metastasis. Importantly, in luminal brain metastases we identify homologous recombination deficiency operative in transcriptomic and genomic data with recurrent breast mutational signatures A, F and K, associated with mismatch repair defects, TP53 mutations and homologous recombination deficiency (HRD) respectively. Utilizing PARP inhibition in patient-derived brain metastatic tumor explants we functionally validate HRD as a key vulnerability. Here, we demonstrate a functionally relevant HRD evident at genomic and transcriptomic levels pointing to genomic instability in breast cancer brain metastasis which is of potential translational significance.
Funding
Breast Cancer Ireland Programme Grant, 18239A01
Science Foundation Ireland Frontiers Award, 19/FFP/6443
National Cancer Institute Outstanding Investigator Award, R35 CA253187
Breast Cancer Research Foundation
Specialized Program of Research Excellence (SPORE) in breast cancer award to the Mayo Clinic (P50 CA116201)
History
Comments
The original article is available at https://www.nature.com/
Published Citation
Cosgrove N, et al. Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities. Nat Commun. 2022;13(1):514.