Abstract
With improvements in systemic therapies, the brain is becoming an increasingly common sanctuary site of metastatic disease in patients with breast cancer. There have been limited improvements in the treatment of brain metastases and current treatment paradigms focus on resection and radiation therapy. As cancer dissemination to the brain currently leads to fatal outcomes developing new therapeutic approaches is paramount. We performed a deep integrated genomic and epigenomic analysis to catalogue the compendium of common and rare events that underlie breast cancer CNS metastasis. Our samples represent breast cancer CNS metastasis, primary breast cancer, non-neoplastic brain and non-neoplastic breast tissue. We performed copy number analysis using array-based comparative genomic hybridization (aCGH, Agilent SurePrint G3 Human High-Resolution Discovery Microarray Kit 1×1M platform); gene expression profiling (GEP) (Agilent, Human GE 4×44 v2 Microarray platform); and DNA methylation analysis (Illumina, HumanMethylation 27 BeadChip). Here we report frequent large chromosomal gains in 1q, 8q, 10p, 21q, and 22q. Frequent large chromosomal deletions were also seen on 8p, and 17p. Focal gains and losses occurred frequently on chromosomes 14, 17 and 22. The PAM50 breast cancer intrinsic classifier was used to classify CNS metastasis tumors. The most common molecular subtypes identified were Luminal B, Her2+/ER negative and Basal-like tumors. Although breast CNS metastasis tumors retained features of their original intrinsic subtype, additional changes were acquired. In addition, DNA methylation analysis of the most variable methylated genes demonstrated epigenetic similarities among the individual molecular subtypes and that overall CNS metastasis is associated with hypermethylation. On average 108 genes had alterations by copy number, gene expression and DNA methylation. Among these are candidate tumor suppressor genes SERPINF1 and SFRP1. Pathway enrichment using Ingenuity Systems revealed a large number of enrichment maps concentrated around cell cycle and G2/M transition. This enrichment contained important cancer genes such AURKA, AURKB and FOXM1. Current studies are ongoing to validate novel candidates genes using cross platform and independent sample cohorts. Characterization of such candidates is expected to lead to novel therapeutic approaches and an enhanced understanding of the biology mediating breast CNS metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B198.
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