TOWARD A MOLECULAR CLASSIFICATION OF HUMAN ASTROCYTOMAS

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DESCRIPTION (Adapted from Applicant's Abstract):Astrocytomas are the most common primary tumors of the central nervous system. However, the classification and grading of astrocytomas remains controversial and curative therapies remain elusive. For instance, the most malignant form of astrocytoma, the glioblastoma multiforme, is heterogeneous in its pathology and in its response to various therapies, yet histopathologic schemes have not been able to subclassify glioblastomas into subgroups that reflect prognosis or therapeutic response. Preliminary data from the investigators laboratory now suggest that molecular genetic analysis may provide a means of better sub- classifying astrocytic tumors. One of the major objectives of this proposal, therefore, is to explore the potential of molecular probes as alternative diagnostic tools in the assessment of astrocytic tumors.Such molecular genetic tools may provide for a genetic classification system which correlates better with prognosis and therapeutic response than do current classification schemes. In close connection with this goal, the investigators propose to identify, isolate, and characterize specific "tumor suppressor" genes on chromosomes 10 and 17p, thought to play a key role in astrocytoma tumorigenesis.This may provide critical new insights into fundamental mechanisms of tumor development and histogenesis in astrocytomas and possibly other human cancers, with potentially important implications for both their diagnosis and treatment. Thus, to obtain a comprehensive overview of the most significant chromosome deletions in a wide variety of astrocytic tumors, the investigators will generate an "allelotype" for astrocytomas of different malignancy grades, using a battery of highly polymorphic DNA markers for each arm of each chromosome, including markers to known "tumor suppressor" loci. Based on their preliminary data, there may be more than one "tumor suppressor" locus on both chromosomes 10 and 17p. They will further narrow and bracket the deleted regions on chromosomes 10 and 17, and possibly identify the "tumor suppressor" genes contained in these deletions. They will substantiate their preliminary observation of a negative correlation between loss of chromosome 10 and loss of the short arm of chromosome 17 (17p) in glioblastomas, suggesting the existence of distinct genetic subtypes of glioblastoma. Furthermore, they will specifically address the role of the p53 "tumor suppressor" gene on 17p in different stages of astrocytoma development. Their preliminary data suggest that EGF receptor amplifications are correlated with loss of chromosome 10, but not with loss of 17p. The ability to examine a larger number of both primary and recurrent specimens for EGF receptor copy number may elucidate whether this aberration delineates a distinct subset of astrocytomas. Finally, all above mentioned genetic aberrations will be correlated a) with a number of histopathologic grading schemes such as WHO and Daumas- Duport classifications, as well as with individual histopathologic features, and b) with long term clinical data, including prognosis (survival, recurrence) and response to certain types of treatment (chemotherapy, radiotherapy). This may eventually lead to the determination of distinct biological and genetic subtypes of astrocytic tumors that better correlate with prognosis and treatment than do traditional classifications.