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Cytogenetic and restriction fragment length polymorphism (RFLP) studies have shown that loss of one entire copy of chromosome 10 is a common genetic event in glioblastoma multiforme, the most malignant glial brain tumor in humans. In a search for submicroscopic deletions, we carried out an RFLP analysis using markers that had been mapped accurately on chromosome 10 by genetic linkage analysis. We studied 30 patients of whom 15 had loss of heterozygosity (LOH) at one or more loci. In seven cases, LOH was found at every informative locus, whereas in two cases extensive deletions were observed involving both the short and long arms. In six other patients, LOH was confined to a portion of the long arm. The smallest region of overlap among these latter six deletions was flanked by markers D10S12 proximally and D10S6 distally, a 33.4 centimorgan region that maps physically near the telomere (q25.1-qter). This region will serve as an important target for future mapping experiments designed to identify a tumor suppressor gene implicated in this lethal form of human cancer.

Primitive neuroectodermal tumors (PNETs) are pediatric brain tumors that result from defects in signaling molecules governing the growth and differentiation of neural progenitor cells. We used the RCAS-TVA system to study the growth effects of three genetic alterations implicated in human PNETs on a subset of neural progenitor cells that express the intermediate filament protein, nestin. The genetic alterations tested were: 1) overexpression of the cellular oncoprotein, MYC; 2) activation of transcription factor, beta-catenin; and 3) haploinsufficiency of Ptc, the hedgehog receptor gene. The RCAS-TVA system uses an avian retroviral vector, RCAS, to target gene expression to specific cell types in transgenic mice. To express exogenous genes in neural progenitor cells, we used Ntv-a mice. In these mice, the Nestin gene promoter drives expression of TVA, the cell surface receptor for the virus. Ectopic expression of MYC, but not activated beta-catenin, promoted the proliferation of neural progenitor cells in culture and in the cerebral leptomeninges in vivo. These effects were equally penetrant in mice with Ptc+/- and Ptc+/+ genetic backgrounds. Although overexpression of MYC is not sufficient to cause intraparenchymal tumors, it may facilitate PNET formation by sustaining the growth of undifferentiated progenitor cells.

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