Dr. Louis states that malignant gliomas are the most common primary human brain tumors, but their classification remains controversial and effective therapies remain elusive for the majority of cases. The common malignant gliomas can be divided into astrocytomas (including the highly malignant glioblastoma), oligodendrogliomas and oligoastrocytomas. He has clarified some of the genetic events that underlie the formation of these tumors, and has begun to correlate such genetic data with clinical and histopathological parameters. Recently, he has shown that certain genetic events may predict chemosensitivity and survival in some gliomas. Despite these advances, however, he states many of the tumor suppressor genes have yet to be identified, the relationships between certain genetic events remain unclear, and the clinical significance of this genetic information has only begun to be tested. He therefore plan to test the hypotheses that: 1) Specific genetic events (loss of chromosomes 1p and 19q, deletions of the CDKN2A/p l6 gene) predict chemosensitivity and survival in human oligodendroglial tumors; 2) Genetic subsets of human glioblastomas are associated with different overall survival; and 3) Astrocytoma tumor suppressor loci reside on chromosomes 11p and 22q. To test these hypotheses, he proposes three specific aims: 1) To analyze three subtypes of oligodendroglial tumor (anaplastic oligodendrogliomas, anaplastic oligo-astrocytomas, and oligodendrogliomas) for chromosome 1p and 19q loss and CDKN2A/pl6 deletion, and correlate these genetic events with chemotherapeutic response and survival; 2) To analyze a large, homogeneous series of glioblastomas for p53 mutations and EGFR amplification, and also for alterations in the CDKN2A/p16-CDK4-RB pathway, and to correlate these genetic events with survival; and 3) To continue genetic characterization of astrocytomas, primarily through detailed analysis of tumor suppressor loci on chromosomes 11p and 22q. He believes that identification of genetic alterations that are integral to glioma tumorigenesis will contribute to a classification system for gliomas, based on their genetic and biologic characteristics, that may more accurately reflect tumor behavior and response to therapy than current histopathological schemes, and that the elucidation of these alterations will provide biological information that may eventually impact on treatments for these malignant tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Pathology B Study Section (PTHB)
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Lively, Tracy (LUGO)
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Massachusetts General Hospital
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Tanaka, Shota; Louis, David N; Curry, William T et al. (2013) Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat Rev Clin Oncol 10:14-26
Rheinbay, Esther; Louis, David N; Bernstein, Bradley E et al. (2012) A tell-tail sign of chromatin: histone mutations drive pediatric glioblastoma. Cancer Cell 21:329-31
Yip, Stephen; Butterfield, Yaron S; Morozova, Olena et al. (2012) Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J Pathol 226:7-16
Louis, David N (2012) The next step in brain tumor classification: ""Let us now praise famous men""… or molecules? Acta Neuropathol 124:761-2
Wakimoto, Hiroaki; Mohapatra, Gayatry; Kanai, Ryuichi et al. (2012) Maintenance of primary tumor phenotype and genotype in glioblastoma stem cells. Neuro Oncol 14:132-44
Kanai, Ryuichi; Rabkin, Samuel D; Yip, Stephen et al. (2012) Oncolytic virus-mediated manipulation of DNA damage responses: synergy with chemotherapy in killing glioblastoma stem cells. J Natl Cancer Inst 104:42-55
Chi, Andrew S; Batchelor, Tracy T; Dias-Santagata, Dora et al. (2012) Prospective, high-throughput molecular profiling of human gliomas. J Neurooncol 110:89-98
Camelo-Piragua, Sandra; Jansen, Michael; Ganguly, Aniruddha et al. (2011) A sensitive and specific diagnostic panel to distinguish diffuse astrocytoma from astrocytosis: chromosome 7 gain with mutant isocitrate dehydrogenase 1 and p53. J Neuropathol Exp Neurol 70:110-5
Dias-Santagata, Dora; Lam, Quynh; Vernovsky, Kathy et al. (2011) BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS One 6:e17948
Rothenberg, S Michael; Mohapatra, Gayatry; Rivera, Miguel N et al. (2010) A genome-wide screen for microdeletions reveals disruption of polarity complex genes in diverse human cancers. Cancer Res 70:2158-64

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