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Modeling Astrocytoma Pathogenesis In Vitro and In Vivo Using Cortical Astrocytes or Neural Stem Cells from Conditional, Genetically Engineered Mice
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Deregulation of the TP53/p14ARF tumor suppressor pathway in low-grade diffuse astrocytomas and its influence on

Takao Watanabe1, Yoichi Katayama, Atsuo Yoshino

  • 1Department of Neurological Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan. takao@med.nihon-u.ac.jp

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|October 29, 2003
PubMed
Abstract

Insights

Disruption of the TP53/p14(ARF) pathway is common in low-grade astrocytomas and linked to a poorer prognosis. However, this finding may not be independently prognostic.

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Genetics

Background:

  • The 9p21 region contains tumor suppressor genes p14(ARF), p15(INK4b), and p16(INK4a), crucial in glioma development.
  • These genes inactivate tumor suppressor pathways, including RB1 and TP53, and are often hypermethylated in low-grade gliomas.
  • Understanding their specific roles and impact on clinical outcomes in diffuse astrocytomas is essential.

Purpose of the Study:

  • To investigate alterations in the RB1/CDK4/p16(INK4a)/p15(INK4b) and TP53/MDM2/p14(ARF) pathways.
  • To analyze the prognostic impact of these pathway alterations in 46 WHO grade II astrocytomas.

Main Methods:

  • Assessed genetic alterations in the RB1 and TP53 tumor suppressor pathways.
  • Analyzed TP53 mutations, p14(ARF) methylation, and alterations in the RB1 pathway components.
  • Correlated genetic findings with clinical behavior and patient prognosis.

Main Results:

  • The TP53/MDM2/p14(ARF) pathway was altered in 70% of cases (TP53 mutation or p14(ARF) methylation).
  • The RB1/CDK4/p16(INK4a)/p15(INK4b) pathway was altered in 13% of cases (methylation or deletion).
  • Combined TP53 mutation and p14(ARF) methylation predicted shorter progression-free survival but lacked independent prognostic value.

Conclusions:

  • Alternative disruption of the TP53/p14(ARF) pathway is frequent in low-grade diffuse astrocytomas.
  • This pathway disruption correlates with a less favorable clinical course.
  • Its prognostic utility is limited when considering established prognostic factors.

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