Malignant astrocytomas are among the most common and deadly brain tumors of childhood. Most affected children die within several years of diagnosis, despite current treatments; however, 20 to 30% respond favorably to therapy and are cured. The basis for these diverse outcomes has been enigmatic, even taking into account clinical and histological factors. In preliminary studies with an institutional cohort of pediatric gliomas, we observed that molecular markers could supplement histological data to refine prognostic assessments. Based on these findings, we began a more extensive study of the cohort of Children's Cancer Group study CCG-945, the largest group of pediatric high-grade gliomas accrued to date. During the prior funding period, specimens from 155 tumors were evaluated in histological and genotyping studies of a broad panel of molecular markers. These studies showed a striking association between outcome and both p53 mutation/overexpression status and MIB1 proliferation index, independent of clinical or histological factors; identified significant differences between molecular features of childhood and adult gliomas; and generated a sizeable resource of microdissected tumor tissue for further analyses. The proposed studies will use this unique resource along with specimens from two new Children's Oncology Group high-grade glioma cohorts (each with 100 patients), in all cases treated with alkylator based chemotherapy, to examine the contribution to treatment response of two of the principal molecular determinants of alkylator resistance, O6-alkylguanine-DNA alkyltransferase (AGT) and mismatch repair (MMR), in the context of other molecular features. We hypothesize that categorization of these tumors by their genomic alterations and resistance phenotype will improve accuracy of prognostic assessments, and reveal patterns of abnormalities distinct from adult gliomas. To test these hypotheses, we propose studies with the following aims: 1) Determine whether genomic alterations affecting p53 function in pediatric highgrade gliomas correlate with therapeutic outcome in the context of other prognostic factors. 2) Examine the association of expression and promoter methylation of AGT with progression-free survival. 3) Assess the frequency and prognostic relevance of microsatellite instability as a correlate of defective mismatch repair in tumor versus paired normal tissue. These markers will be evaluated in the context of conventional prognostic factors, such as histology, to determine their utility for biologically classifying childhood malignant gliomas. Relevance: Taken together, the proposed studies will provide new insights into the molecular categorization of pediatric high-grade gliomas. This work will establish a foundation for risk-adapted stratification and treatment planning for children with these tumors. ? ? ? ? ? ? ?
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