Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities.
Nicola CosgroveDamir VarešlijaStephen KeelanAshuvinee ElangovanJennifer M AtkinsonSinéad CocchigliaFiona T BaneVikrant SinghSimon J FurneyChunling HuJodi M CarterSteven N HartSiddhartha YadavMatthew P GoetzArnold D K HillSteffi OesterreichAdrian V LeeFergus J CouchLeonie S YoungPublished in: Nature communications (2022)
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.
Keyphrases
- brain metastases
- resting state
- small cell lung cancer
- white matter
- dna repair
- dna damage
- functional connectivity
- copy number
- cerebral ischemia
- genome wide
- single cell
- transcription factor
- squamous cell carcinoma
- electronic health record
- public health
- multiple sclerosis
- case report
- climate change
- high resolution
- oxidative stress
- young adults
- blood brain barrier
- brain injury
- single molecule