Detection of p16, RB, CDK4, and p53 gene deletion and amplification by fluorescence in situ hybridization in 96 gliomas

Inactivation of the p53 gene is a common early event of astrocytoma tumorig enesis. Alternatively, since the p16, retinoblastoma (RB), and CDK4 genes h ave been implicated in malignant progression, detection of losses or amplif ications of these genes in gliomas could be diagnostically, prognostically, and therapeutically important. We obtained smear preparations from 96 diff use gliomas and 10 nonneoplastic specimens. Dual-color fluorescence in situ hybridizations using paired probes for CEN9/p16, CEN8/RB, CEN17/p53, and C EN12/CDK4 were performed and revealed expected frequencies of abnormalities , except for p53 losses, which were low (7%). The latter supports the conce pt that p53 inactivation usually occurs by mitotic recombination. Detected abnormalities of the p16/RB/CDK4 pathway were highly associated with astroc ytic differentiation and were univariately associated with decreased patien t survival. However; only patient age and histologic classification retaine d statistical significance on multivariate analysis. We conclude that in di ffuse gliomas, p16/RB/CDK4 abnormalities are markers of astrocytic phenotyp e. Thus, their detection by fluorescence in situ hybridization may have dia gnostic usefulness in cases with equivocal morphologic features. Although o ur numbers are small, we find no additional prognostic significance to thes e genetic abnormalities once age, grade, and oligodendroglial histology are taken into account.