Integrated Genomic and Epigenomic Analysis of Breast Cancer Brain Metastasis

Abstract

The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain 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 brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain 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 brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.

Epigenetics of Breast Cancer: DNA Methylome and Global Histone Modifications

“…Similar to primary tumors, subtypes of metastases were discriminated by 90 differentially methylated CpGs. Basal-like metastases were found to have the lowest methylation levels consistent with the primary tumor data [ 38 ]. The differences between metastases and matched primary tumors were not that striking.…”

“…Thus, its molecular characterization has long been a focus of interest. To understand the landscape of breast brain metastasis, DNA methylation profi le was analyzed in 32 metastases, 12 non-neoplastic breast tissue and 15 nonneoplastic brain tissue [ 38 ]. 425 CpGs were found to be differentially methylated in metastases, majority being hypermethylated.…”

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

“…Moreover, the genetic profiles of extracranial and lymph node metastases were highly divergent from those identified in BM. An independent study analysing genomic profiling, gene expression and DNA methylation of BM revealed highly specific BM molecular profiles in BC patients [57]. Therefore, individualised molecular biological profiling of BM is clinically relevant for targeted therapy approaches and treatment algorithms tailored to the person.…”

A class of genes in the HER2 regulon that is poised for transcription in breast cancer cell lines and expressed in human breast tumors

“…Of 113 such class of genes, 65 are up regulated and 48 are down regulated in HER2 + vs HER2 − primary breast cancer. Among up regulated genes are SDC1[32], DUSP6 [33], VASP [34], IDH2 [35], DDR1 [36], GPC1 [37], SQSTM1 [38], and among down regulated genes are RHEB [39], IRS-2 [40], HSPB2 [41] and RAP1A [42]. Several of these genes have been reported previously to be associated with high levels of HER2 expression in human breast and ovarian neoplasia (Table 3).…”