The central nervous system (CNS) is a common site of metastatic disease in patients with breast cancer and has few therapeutic options with dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer CNS metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our CNS metastasis cohort. While overall methylation levels were increased in breast cancer CNS metastasis, basal-like CNS metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast CNS metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies. Three sample-types: 35 Breast Brain Metastasis samples, 10 Non-Neoplastic Brain samples, and 10 Non-Neoplastic Breast samples.
|Date made available||2014|