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 Blood, 15 March 2008, Vol. 111, No. 6, pp. 3200-3210.
Prepublished online as a Blood First Edition Paper on January 9, 2008; DOI 10.1182/blood-2007-10-119099.

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NEOPLASIA

Pathway analysis of primary central nervous system lymphoma

Han W. Tun1, David Personett2, Karen A. Baskerville2, David M. Menke3, Kurt A. Jaeckle4, Pamela Kreinest5, Brandy Edenfield5, Abba C. Zubair3, Brian P. O'Neill6, Weil R. Lai7, Peter J. Park7, and Michael McKinney2

Departments of1 Hematology and Oncology, 2 Molecular Pharmacology and Therapeutics, 3 Pathology, 4 Neurology, and 5 Cancer Biology, Mayo Clinic Jacksonville, FL; 6 Department of Neurology, Mayo Clinic Rochester, MN; and 7 Harvard-Partners Center for Genetics and Genomics, Boston, MA

Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a "CNS signature." Pathway analysis with the program SigPathway revealed that PCNSL is characterized notably by significant differential expression of multiple extracellular matrix (ECM) and adhesion-related pathways. The most significantly up-regulated gene is the ECM-related osteopontin (SPP1). Expression at the protein level of ECM-related SPP1 and CHI3L1 in PCNSL cells was demonstrated by immunohistochemistry. The alterations in gene expression can be interpreted within several biologic contexts with implications for PCNSL, including CNS tropism (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell subtype (MUM1), lymphoproliferation (SPP1, TCL1A, CHI3L1), aggressive clinical behavior (SPP1, CHI3L1, MUM1), and aggressive metastatic cancer phenotype (SPP1, CHI3L1). The gene expression signature discovered in our study may represent a true "CNS signature" because we contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.


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