Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2) = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.
Large terrestrial carnivores have undergone some of the largest population declines and range reductions of any species, which is of concern as they can have large effects on ecosystem dynamics and function.1-4 The jaguar (Panthera onca) is the apex predator throughout the majority of the Neotropics; however, its distribution has been reduced by >50% and it survives in increasingly isolated populations.5 Consequently, the range-wide management of the jaguar depends upon maintaining core populations connected through multi-national, transboundary cooperation, which requires understanding the movement ecology and space use of jaguars throughout their range.6-8 Using GPS telemetry data for 111 jaguars from 13 ecoregions within the four biomes that constitute the majority of jaguar habitat, we examined the landscape-level environmental and anthropogenic factors related to jaguar home range size and movement parameters. Home range size decreased with increasing net productivity and forest cover and increased with increasing road density. Speed decreased with increasing forest cover with no sexual differences, while males had more directional movements, but tortuosity in movements was not related to any landscape factors. We demonstrated a synergistic relationship between landscape-scale environmental and anthropogenic factors and jaguars' spatial needs, which has applications to the conservation strategy for the species throughout the Neotropics. Using large-scale collaboration, we overcame limitations from small sample sizes typical in large carnivore research to provide a mechanism to evaluate habitat quality for jaguars and an inferential modeling framework adaptable to the conservation of other large terrestrial carnivores.