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Deregulation of the p14^ARF/MDM2/p53 Pathway Is a Prerequisite for Human Astrocytic Gliomas with G₁-S Transition Control Gene Abnormalities¹

Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom [K. I., E. E. S., V. P. C], and Ludwig Institute for Cancer Research and Unit of Tumorpathology, Department of Oncology and Pathology, Karolinska Hospital, 171 76 Stockholm, Sweden [K. I., M. B. B., H. M. G., E. E. S., A. M., V. P. C.]

Deregulation of G₁-S transition control in cell cycle is one of the important mechanisms in the development of human tumors including astrocytic gliomas. We have previously reported that approximately two-thirds of glioblastomas (GBs) had abnormalities of G₁-S transition control either by mutation/homozygous deletion of RB1 or CDKN2A (p16^INK4A), or amplification of CDK4 (K. Ichimura et al., Oncogene, 13: 1065–1072, 1996). However, abnormalities of G₁-S transition control genes may induce p53-dependent apoptosis in cells. Recent investigations suggest that p14^ARF is induced in response to abnormal cell cycle entry and results in p53 accumulation by inhibiting MDM2-mediated transactivational silencing and degradation of p53. To investigate the roles of the G₁-S transition control system and the p14^ARF/MDM2/p53 pathway in the development of astrocytic gliomas, we examined abnormalities of genes involved in these regulatory pathways in a total of 190 primary human astrocytic gliomas of different malignancy grades [136 GBs, 39 anaplastic astrocytomas (AAs) and 15 astrocytomas (As)]. Sixty-seven percent of GBs (91/136) and 21% of AAs (8/39) had abnormalities of the G₁-S control system either by mutation/homozygous deletion of RB1, CDKN2A or CDKN2B, or amplification of CDK4. Seventy-six percent of GBs (103 of 136), 72% of AAs (28 of 39), and 67% of As (10 of 15) had deregulated p53 pathway either by mutation of TP53, amplification of MDM2, or homozygous deletion/mutation of p14^ARF. When all of the data were combined and compared, 96% of GBs (87 of 91) and 88% of AAs (7 of 8) with abnormal G₁-S transition control also had deregulated p53 pathway. Thus, we demonstrate that deregulation of the G₁-S transition control system was almost always accompanied by inactivation of the p53 pathway, clearly illustrating the cooperative roles of these two systems in the development/progression of primary human astrocytic gliomas.

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