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[Cancer Research 63, 6613-6625, October 15, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Classification of Human Astrocytic Gliomas on the Basis of Gene Expression

A Correlated Group of Genes with Angiogenic Activity Emerges As a Strong Predictor of Subtypes1 ,2

Sophie Godard, Gad Getz, Mauro Delorenzi, Pierre Farmer, Hiroyuki Kobayashi, Isabelle Desbaillets, Michimasa Nozaki, Annie-Claire Diserens, Marie-France Hamou, Pierre-Yves Dietrich, Luca Regli, Robert C. Janzer, Philipp Bucher, Roger Stupp, Nicolas de Tribolet, Eytan Domany and Monika E. Hegi3

Laboratory of Tumor Biology and Genetics [S. G., H. K., I. D., M. N., A-C. D., M-F. H., N. d. T., M. E. H.] of the Department of Neurosurgery [L. R., N. d. T.], Multidisciplinary Oncology Center [R. S.], and Division of Neuropathology [R. C. J.], University Hospital (CHUV), 1011 Lausanne, Switzerland; Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel [G. G., E. D.]; Swiss Institute of Bioinformatics [M. D., P. F., P. B.]; and NCCR Molecular Oncology [M. D., P. F., M. E. H.], Swiss Institute for Experimental Cancer Research, 1066 Epalinges, Switzerland; and Department of Oncology, Hôpital Universitaire Genève, Switzerland [P-Y. D.]

The development of targeted treatment strategies adapted to individual patients requires identification of the different tumor classes according to their biology and prognosis. We focus here on the molecular aspects underlying these differences, in terms of sets of genes that control pathogenesis of the different subtypes of astrocytic glioma. By performing cDNA-array analysis of 53 patient biopsies, comprising low-grade astrocytoma, secondary glioblastoma (respective recurrent high-grade tumors), and newly diagnosed primary glioblastoma, we demonstrate that human gliomas can be differentiated according to their gene expression. We found that low-grade astrocytoma have the most specific and similar expression profiles, whereas primary glioblastoma exhibit much larger variation between tumors. Secondary glioblastoma display features of both other groups. We identified several sets of genes with relatively highly correlated expression within groups that: (a) can be associated with specific biological functions; and (b) effectively differentiate tumor class. One prominent gene cluster discriminating primary versus nonprimary glioblastoma comprises mostly genes involved in angiogenesis, including VEGF fms-related tyrosine kinase1 but also IGFBP2, that has not yet been directly linked to angiogenesis. In situ hybridization demonstrating coexpression of IGFBP2 and VEGF in pseudopalisading cells surrounding tumor necrosis provided further evidence for a possible involvement of IGFBP2 in angiogenesis. The separating groups of genes were found by the unsupervised coupled two-way clustering method, and their classification power was validated by a supervised construction of a nearly perfect glioma classifier.




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Copyright © 2003 by the American Association for Cancer Research.