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Short Postoperative Survival for Glioblastoma Patients with a Dysfunctional Rb1 Pathway in Combination with No Wild-type PTEN¹

Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Addenbrooke’s Hospital, Box 231, Cambridge CB2 2QQ, United Kingdom [E. E. S., L. L., K. I., V. P. C.], and Ludwig Institute for Cancer Research and Department of Oncology-Pathology, Karolinska Hospital, 171 76 Stockholm, Sweden [L. M. B., B. R. N., H. M. G.]

Purpose: Glioblastoma (GB, WHO grade IV) is the most common primary brain tumor in adults. Survival is typically <1 year but varies between a few months and a couple of years. The aim of the study was to find novel genetic prognostic factors in a well-defined GB series.

Experimental Design: The survival data on 129 GBs were correlated with the results of a detailed analysis of 9 genes. These included 3 genes coding for proteins in the p53 pathway (i.e., TP53, p14^ARF, and MDM2), 4 in the Rb1 pathway (i.e., CDKN2A, CDKN2B, RB1, and CDK4), as well as PTEN and epidermal growth factor receptor.

Results: We found that abnormalities in any of the four genes (CDKN2A, CDKN2B, RB1, and CDK4) coding for components of the Rb1 pathway were associated with shorter survival (P = 0.002). In combination with loss of wild-type PTEN, the association was even stronger (P < 0.001), the median survival being 166 days as compared with the group without these abnormalities where the median postoperative survival was 437 days. The survival difference remained statistically significant in Cox’ regression analysis adjusting for age (P = 0.012).

Conclusions: The findings indicate that knowledge of the molecular genetic abnormalities in GBs provides important data in assessing individual patients. As additional advances in our understanding of the molecular genetics and cell biology of gliomas are made, in addition to providing prognostic information, such data may also provide targets for innovative therapy in the individual case.

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