Gene expression profiling suggests primary central nervous system lymphomas to be derived from a late germinal center B cell

Abstract

To characterize the molecular origin of primary lymphomas of the central nervous system (PCNSL), 21 PCNSLs of immunocompetent patients were investigated by microarray-based gene expression profiling. Comparison of the transcriptional profile of PCNSL with various normal and neoplastic B-cell subsets demonstrated PCNSL (i) to display gene expression patterns most closely related to late germinal center B cells, (ii) to display a gene expression profile similar to systemic diffuse large B-cell lymphomas (DLBCLs) and (iii) to be in part assigned to the activated B-cell-like (ABC) or the germinal center B-cell-like (GCB) subtype of DLBCL.

Figure 1

Relatedness of the gene expression profile of PCNSL to normal B-cell populations. (a-e) Assessment of the gene expression profile of PCNSL as compared to normal B-cell populations. Genes differentially expressed between two groups of samples are calculated by supervised analysis. Signature of naive (N) and memory (M) B cells (N/M) versus germinal center centroblasts and centrocytes (GC) (a), of M B cells versus N B cells (b), of N B cells versus GC B cells (c) and of M B cells versus GC (d). The expression of the selected genes was investigated in PCNSL displayed on the right side of each matrix (a-d). (e) Classification according to the respective cell type was used to calculate the assignment of PCNSL to two normal B-cell subtypes. A cell-type classification is used to measure the relatedness of PCNSL to different normal B-cell subsets. The gray area marks 95% of confidence: The P value decreases with increasing distance from the x axis. (f) Unsupervised hierarchical clustering of gene expression values from PCNSL and DLBCL excluding the top 476 genes highly expressed in normal brain as compared to lymphatic tissue. Unsupervised analysis was performed in 21 cases of PCNSL and 19 cases of systemic DLBCL. The 40 tumor samples are clustered according to their expression of 173 genes. DLBCL, diffuse large B-cell lymphoma;PCNSL, primary central nervous system lymphoma.

Figure 2

Expression analysis of genes previously reported to be differentially expressed between PCNSL and systemic DLBCL. Rubenstein et al.¹⁴ have described 462 ESTs to be differentially expressed between PCNSL and systemic DLBCL with 29 genes to discriminate most significantly. A total of 133 tags of these ESTs were represented on the HG-U95Av2 microarray. The expression profile of these 133 tags was evaluated in our group of PCNSL demonstrating that they did not differ from systemic DLBCL in the vast majority. VCAM-1 and CCL19 were the only genes, which were downregulated in PCNSL as compared to DLBCL. DLBCL, diffuse large B-cell lymphoma; PCNSL, primary central nervous system lymphoma.