An Exploration of the Medulloblastoma and Glioblastoma Genomes: A Critical Analysis of Candidate Cancer Genes as Potential Molecular Targets for Diagnostics and Therapeutics
Update - 6/2014:
This ALSF-funded study established important groundwork for future studies in glioblastomas (GBM) and medulloblastomas (MB) as the targeted genetic analyses that were initially proposed were expanded to include all protein-encoding genes. This project led to the first whole exome sequencing (WES) analysis of any pediatric solid tumor (MB), which revealed a number of critical genes not previously known to be altered in MB, most notably inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 and MLL3 (Parsons et al. Science 2011). These results emphasized the important connection between genetic alterations in the cancer genome and epigenetic pathways and identified new avenues for research and disease management in MB patients. In addition, they provided a novel view of the genetic landscape of these tumors, contributing to an improved molecular classification (Taylor et al. Acta Neuropathol 2012), and identified novel targets for diagnostic and therapeutic applications. Similarly, the analysis of GBM produced a novel view of the genetic landscape of these tumors and identified the isocitrate dehydrogenase genes IDH1 and IDH2 as critical glioma genes, opening a new avenue of GBM research that has led to diagnostic tests that are currently being used in the neuro-oncology clinic and the development of investigational targeted therapies (Parsons et al. Science 2008; Yan et al. New Eng J Med 2009; Yan et al. Cancer Res 2009; Reitman et al. Cancer Cell. 2010; Parsons et al. Oncotarget 2010).
Dr. Parsons has continued his research into the genomics of both CNS and non-CNS pediatric solid tumors and currently focuses on the clinical application of these technologies for children with cancer. He went on to receive an ALSF A-Award for continued glioma research and has received funding from the NIH (NHGRI/NCI) and the Cancer Prevention and Research Institute of Texas (CPRIT) as well as numerous foundations. Most recently, he is the principal investigator from Baylor College of Medicine for the first multi-institutional collaborative Stand Up 2 Cancer / St. Baldrick’s Foundation Pediatric Dream Team Translational Grant.
Parsons DW, Jones S, Zhang X et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321(5897): 1807-12. PubMed PMID: 18772396; PubMed Central PMCID: PMC2820389.
Parsons DW. The evolving picture of the glioblastoma genome. Oncotarget 2010; 1(4): 237-8. PubMed PMID: 21304175.
Parsons DW, Li M, Zhang X et al. The Genetic Landscape of the Childhood Cancer Medulloblastoma. Science 2011; 331(6016):435-9. PubMed PMID: 21163964.
Reitman ZJ, Parsons DW, Yan H. IDH1 and IDH2: Not your typical oncogenes. Cancer Cell 2010;17(3):215-6. PubMed PMID: 20227034.
Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 2012; 123(4):465-72. PubMed PMID: 22134537; PubMed Central PMCID: PMC3306779.
Yan H, Parsons DW et al. IDH1 and IDH2 mutations in gliomas. New Eng J Med 2009; 360(8): 765-73. PubMed Central PMCID: PMC2820383.
Yan H., Bigner D.D., Velculescu V., Parsons DW. Mutant metabolic enzymes are at the origin of gliomas. Cancer Res 2009; 69(24): 9157-9. PubMed PMID: 19996293; PubMed PMID: 19228619; PubMed Central PMCID: PMC2820383.
Cancer is a genetic disease caused by sequential accumulation of mutations in oncogenes and tumor suppressor genes. The identification and characterization of such mutations has enabled the development of molecular diagnostics as well as targeted molecular therapies which have been utilized to achieve remarkable clinical benefit in the treatment of specific tumor types. The vast majority of genetic alterations causing most human cancers remain unknown, however, as demonstrated by the results of our recent analysis of the breast and colon cancer genomes, which revealed a remarkable level of mutational complexity within these two tumor types. This analysis identified a number of candidate cancer genes, the majority of which had not previously been linked to neoplasia.
The objective of this study is to analyze a large panel of medulloblastomas and glioblastomas for alterations in a select group of candidate cancer genes, with an ultimate goal of rapidly identifying specific genes and pathways which may serve as targets for novel molecular diagnostics and therapies in these tumor types. This will specifically be accomplished by integrating the results of DNA sequencing-based mutation analyses of the selected candidate cancer genes with gene copy number data obtained on the same panel of brain tumors using high-density SNP genotyping. A systems analysis of the combined mutation and gene copy number data will be conducted in order to select the most potentially clinically relevant genes, functional groups, and genetic pathways for further study. Finally, enotype:phenotype analysis of any commonly mutated genes will be performed, including their relation to medulloblastoma histologic subtype and patient outcome as well as glioma histologic grade.