Malignant astrocytoma is one of the most common and deadly primary central nervous system tumors of childhood. Most affected children exhibit relentless disease progression despite a combination of surgical and adjuvant treatment and die within several months of diagnosis; however, 30 to 40 percent respond favorably to such therapy and appear to be cured. The basis for the widely differing outcomes in children with malignant astrocytomas has been largely an enigma, even taking into account clinical prognostic factors, which has hampered efforts at therapeutic stratification. In preliminary studies, the investigators hypothesized that molecular and immunohistochemical markers of tumor biology would provide a means for supplementing clinical and histological information as a way to refine prognostic assessments. To test their hypothesis, the investigators conducted a retrospective institutional study investigating the prognostic utility of a variety of potential markers in a cohort of well-characterized pediatric high- grade gliomas. Their preliminary data indicated a strong association between progression-free and overall survival and p53 mutation and expression status, MIB-1 proliferation index, and basic fibroblast growth factor immunoreactivity in children with these tumors. In the current study, the authors propose to test further the validity of their hypothesis by examining the prognostic utility of a selected panel of immunohistochemical and genotypic markers in a larger cohort of childhood malignant gliomas to define conclusively factors that are independently predictive of outcome. The investigators are in a unique position to address this issue, both because of institutional expertise in tumor marker studies and because of their access to the histological specimens of the largest multi-institutional cohort of children with malignant gliomas accrued to date (Childhood Cancer group (CCG) study 945). Their cohort study is endorsed by the CCG (study designated as CCG-B0051), who will be providing statistical support and specimen retrieval.
The aims of this study are: 1) to determine whether TP53 mutations have an adverse association with therapeutic outcome; 2) to determine whether MIB-1 proliferative index supplements histology as a predictor of outcome; and 3) to examine the applicability of other potential markers, particularly basic FGF and bcl-2 overexpression and chromosome 10 deletion, as correlates of tumor behavior. These data will be evaluated in the context of other prognostic factors to develop a means for biologically stratifying malignant gliomas. Taken together, this work would provide new insights into the biological correlates of glioma behavior and would establish a basis for identifying groups of patients who may respond poorly to current therapy and might be appropriate candidates for therapeutic approaches.
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