Whole-genome expression profiling of brain metastases from melanoma (BrMM) provides preliminary insights into its biology and mechanisms of development.

Abstract

8515 Background: BrMM accounts for a major fraction of the mortality from melanoma and little is known about the biology of BrMM or its association with extracranial metastases (EcMM) and primary melanoma (PrM). This would provide insights about BrMM pathogenesis and lead to better prognostic and therapeutic targets. We hypothesize that BrMM differ from EcMM and PrMs in gene expression levels. These signatures will provide insight to the pathogenesis and lead to better prognostic and therapeutic targets. Methods: We have performed whole genome expression profiling (DASL assay, Illumina; 28,688 genes) of formalin-fixed paraffin-embedded (FFPE) tissue blocks corresponding to paired specimens (BrMM and EcMM) from patients (pts) undergoing craniotomy at UPCI. We performed class comparison analysis using paired t tests to identify differentially expressed genes. Results are presented as the ratio of the geometric mean of EcMM/BrMM. Results: Paired analysis of FFPE tumor blocks from 12 pts has been accomplished (n=24). 187 genes were differentially (p<0.05) expressed between BrMM and EcMM. The table shows gene categories of most significantly dysregulated genes. We confirmed that upregulation of GFAP in BrMM derives from melanoma cells and not normal brain using immunohistochemical analysis of GFAP protein in BrMM, EcMM, and PrM from the same pt. Conclusions: The upregulation of neuronal differentiation genes in BrMM underscores the potential of melanoma cells to transdifferentiate (plasticity) although the clinical significance is currently unknown. The upregulation of immune tolerance and ECM remodeling genes in EcMM challenges the prevailing notion that BrMM is the last step in the metastatic cascade. Profiling PrM is underway. Function EcMM/BrMM Extracellular matrix (ECM) remodeling Cartilage intermediate protein 6.2 Matrix metallopeptidase 9 5.3 Cartilage oligomeric matrix protein 4.9 Microfibrillar-associated protein 5 3.2 Neural differentiation/function Gliomedin 0.15 Glutamate receptor, metabotropic 3 0.23 Glial fibriallary acidic protein (GFAP) 0.26 Immune tolerance Chemokine ligand 19 3.6 Chemokine ligand 21 3.6 CTLA4 2.4