MALIGNANT ASTROCYTOMAS WITH HOMOZYGOUS CDKN2 P16 GENE DELETIONS HAVE HIGHER KI-67 PROLIFERATION INDEXES/

p16 is involved in a cell-cycle regulatory cascade that includes cycli n-dependent kinase 4 (cdk4), cyclin D1 and pRb. Alterations of each of these components have been described in primary human glioblastoma mu ltiforme (GBM) or GBM cell lines, and alterations of the individual co mponents of this pathway appear inversely correlated with one another. While this suggests that disruption of any individual component has s imilar oncogenic effects, homozygous deletions of the CDKN2/p16 gene a re the most common genetic alteration. We investigated the relationshi p between homozygous CDKN2/p16 deletions and cellular proliferation in 50 primary astrocytomas (2 WHO grade I pilocytic astrocytoma, 15 grad e II astrocytomas, 20 grade III anaplastic astrocytomas and 13 grade I V GBMs). Using a comparative multiples PCR assay, homozygous deletions of the CDKN2/p16 gene were detected in 5 anaplastic astrocytomas (25% ) and 6 GBMs (46%), but in none of the lower-grade tumors. Ki-67 immun ohistochemistry was used to assess the number of proliferating cells i n the same samples used for molecular genetic analysis. In both anapla stic astrocytomas and GBMs, Ki-67 proliferation indices were significa ntly higher in tumors with CDKN2/p16 deletions (20%) than in those wit hout deletions (10%; p=0.0001). These results suggest that homozygous CDKN2/p16 deletions in high-grade astrocytomas may have a more deleter ious effect on cell cycle control than the other aberrations in the p1 6-cdk4-cyclin D1-pRb pathway, and may provide one explanation for why homozygous CDKN2/p16 deletions are more common genetic events in high- grade astrocytomas than RB mutations or CDK4 amplification.