Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

摘要: Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy critically under-utilized, our understanding of mechanisms underpinning metastatic outgrowth in limited. To address these deficiencies, we investigated genomic transcriptomic landscapes 36 BMs from breast, lung, melanoma oesophageal cancers, using DNA copy-number analysis exome- RNA-sequencing. The key findings were as follows. (a) Identification novel candidates possible roles BM development, including significantly mutated genes DSC2, ST7, PIK3R1 SMC5, repair, ERBB-HER signalling, axon guidance protein kinase-A signalling pathways. (b) Mutational signature was applied to successfully identify primary cancer type two unknown origins. (c) Actionable alterations identified 31/36 (86%); one case retrospectively ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment HER2-positivity across four consecutive deposits by IHC SISH, resulting deployment HER2-targeted patient. (d) In ERBB/HER pathway, expression correlated ERBB3 (r(2)  = 0.496; p < 0.0001) HER3 HER4 frequently activated an independent cohort 167 archival seven types: 57.6% 52.6% cases phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. ligands NRG1/2 barely detectable RNAseq, NRG1 (8p12) loss 63.6% breast cancer-BMs, suggesting a microenvironmental source ligand. summary, this first study characterize BM. data revealed candidates, potential clinical applications profiling resectable BMs, highlighted possibility therapeutically targeting HER3, which broadly over-expressed site systemic therapy.