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Deregulation of the TP53/p14^ARF Tumor Suppressor Pathway in Low-Grade Diffuse Astrocytomas and Its Influence on Clinical Course

Department of Neurological Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan

Purpose: The chromosome 9p21 region harbors three tumor suppressor genes, p14^ARF, p15^INK4b, and p16^INK4a, all of which can be targets for hypermethylation-associated inactivation in low-grade gliomas. p16^INK4a and p15^INK4b are critically involved in the RB1 pathway, whereas p14^ARF acts as an upstream regulator of the TP53 pathway. The role of each tumor suppressor pathway in low-grade diffuse astrocytomas and their relationships with clinical behavior remain to be elucidated.

Experimental Design: We assessed the alterations of the RB1/CDK4/p16^INK4a/p15^INK4b and the TP53/MDM2/p14^ARF pathways in 46 WHO grade II astrocytomas and analyzed their impact on prognosis.

Results: The TP53/MDM2/p14^ARF pathway was altered in 32 of 46 cases (70%) by either TP53 mutation (25 cases) or p14^ARF methylation (9 cases). The RB1/CDK4/p16^INK4a/p15^INK4b pathway was disrupted in 6 of 46 cases (13%) by either RB1 methylation (1 case), p16^INK4a methylation (3 cases), or p15^INK4b methylation or homozygous deletion (3 cases). Generally speaking, individual tumors thus tended to display alteration of only one component from both pathways. Any independently analyzed genetic alteration failed to provide statistically prognostic information. The alternate or simultaneous presence of TP53 mutation and p14^ARF methylation emerged as a univariate predictor of a shorter progression-free survival (P = 0.0456) but was not statistically significant when age and extent of surgery were included in the analysis.

Conclusions: Alternative disruption of the TP53/p14^ARF pathway represents a frequent event in low-grade diffuse astrocytomas and correlates with an unfavorable clinical course. However, its value is unlikely to include prognostic utility that is independent of other conventional prognostic factors.

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