Human cancer is caused by the accumulation of mutations and copy number changes in oncogenes and tumor suppressor genes. To understand what these genetic changes are, we performed the first genome-wide sequencing of human cancers including breast, colorectal, brain (glioblastoma and medulloblastoma), and pancreatic cancers.
In general, our survey of the genomic landscapes of cancers revealed two populations of genes: 1) few commonly altered gene “mountains” and 2) many gene “hills” that are altered at low frequency. Using information such as sequence similarity, membership in known functional groups and pathways, and predicted interactions with other proteins, as well as statistical and bioinformatics methods, we identified functional groups and pathways that were enriched for mutated genes in the different tumor types. In addition, we also discovered characteristics unique to particular tissue types. For example, in pancreatic cancers, we found that the majority of alterations defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors. Furthermore, in patients with familial pancreatic cancer, we revealed that PALB2 contained germline, truncating mutation in approximately 4% of patients. In glioblastoma multiforme (GBM), we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. In medulloblastoma (MB), inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. Global and tumor-specific discoveries pave the way for earlier diagnosis, more accurate prognosis, and more effective therapeutics.
In addition to human cancer genomes, we also describe the complete genome and transcriptome sequencing of the anti-tumor agent Clostridium novyi-NT. We have determined the 2.55-Mb genomic sequence of C. novyi-NT, identifying a new type of transposition and 139 genes that do not have homologs in other bacteria. This provides a high-resolution map for a biologic agent that can be modified for maximize therapeutic effect.
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 72/10, Dissertation Abstracts International|
|Subjects:||Genetics, Pharmacology, Medicine, Bioinformatics, Oncology|
|Keywords:||Anti-tumor agents, Brain cancer, Breast cancer, C. novyi-NT, Colorectal cancer, Pancreatic cancer|
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