Cancer Gets Its Complexity Scrutinized

Studies spot numerous undiscovered gene alterations in pancreatic and brain cancers Thursday, 04 September 2008 It has long been understood among cancer researchers, that tumours are almost an individualized genetic disease. However, the complexity of the genetic changes occurring while a tumour is growing has not been possible to appreciate, even less study before. Now, several studies are aiming at exactly this goal: to get a complete genetic picture of cancers and tumours, of the same group individualised. Maps of individual breast cancer and colorectal cancer genomes were published last year, in part by a team at the Johns Hopkins Kimmel Cancer Center. Now, the same team has deciphered the complete genetic blueprint for lethal pancreatic cancer and brain cancer. Believed to be the most comprehensive result to date for any tumour type, the new map evaluated mutations in virtually all known human protein-encoding genes, comprised of more than 20,000 genes, in 24 pancreatic cancers and 22 brain cancers. A core set of regulatory gene processes and pathways, about a dozen for each tumour type, were found to be altered in the majority of tumours studied by the researchers. In pancreatic cancer, these 12 pathways, including those linked to DNA damage control, cell maturation, and tumour invasion, were altered in 67 percent to 100 percent of tumours. "This perspective changes the way we think about solid tumours and their management, because drugs or other agents that target the physiologic effects of these pathways, rather than individual gene components, are likely to be the most useful approach for developing new therapies," says Bert Vogelstein, M.D., co-director of the Ludwig Center at Johns Hopkins and a Howard Hughes Medical Institute investigator. In addition to the pathway discoveries, a number of individual mutated genes were identified, including 83 cancer genes in pancreatic cancer and 42 in the most lethal form of brain cancer, glioblastoma multiforme (GBM). Additionally, 70 genes that were dramatically over-expressed in either cancer encode proteins that are on the surface of cells or secreted, making them potential diagnostic and screening targets. A parallel study from the Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, together with their collaborating investigators at 18 institutions and organizations, report an array of broken, missing, and overactive genes — some implicated for the first time — in glioblastoma, the most common and deadly form of adult brain cancer. The large-scale combing of the brain cancer genome confirms the key roles of some previously known mutated genes and implicates a variety of other genetic changes that may be targets for future therapies. References: An Integrated Genomic Analysis of Human Glioblastoma Multiforme D. Williams Parsons, Siân Jones, Xiaosong Zhang, Jimmy Cheng-Ho Lin, Rebecca J. Leary, Philipp Angenendt, Parminder Mankoo, Hannah Carter, I-Mei Siu, Gary L. Gallia, Alessandro Olivi, Roger McLendon, B. Ahmed Rasheed, Stephen Keir, Tatiana Nikolskaya, Yuri Nikolsky, Dana A. Busam, Hanna Tekleab, Luis A. Diaz Jr., James Hartigan, Doug R. Smith, Robert L. Strausberg, Suely Kazue Nagahashi Marie, Sueli Mieko Oba Shinjo, Hai Yan, Gregory J. Riggins, Darell D. Bigner, Rachel Karchin, Nick Papadopoulos, Giovanni Parmigiani, Bert Vogelstein, Victor E. Velculescu, and Kenneth W. Kinzler Published online September 4 2008; 10.1126/science.1164382 Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses Siân Jones, Xiaosong Zhang, D. Williams Parsons, Jimmy Cheng-Ho Lin, Rebecca J. Leary, Philipp Angenendt, Parminder Mankoo, Hannah Carter, Hirohiko Kamiyama, Antonio Jimeno, Seung-Mo Hong, Baojin Fu, Ming-Tseh Lin, Eric S. Calhoun, Mihoko Kamiyama, Kimberly Walter, Tatiana Nikolskaya, Yuri Nikolsky, James Hartigan, Douglas R. Smith, Manuel Hidalgo, Steven D. Leach, Alison P. Klein, Elizabeth M. Jaffee, Michael Goggins, Anirban Maitra, Christine Iacobuzio-Donahue, James R. Eshleman, Scott E. Kern, Ralph H. Hruban, Rachel Karchin, Nickolas Papadopoulos, Giovanni Parmigiani, Bert Vogelstein, Victor E. Velculescu, and Kenneth W. Kinzler Published online September 4 2008; 10.1126/science.1164368 Comprehensive genomic characterization defines human glioblastoma genes and core pathways The Cancer Genome Atlas Research Network Nature advance online publication 4 September 2008, doi:10.1038/nature07385 Articles from EurekAlert!: Comprehensive genetic blueprints revealed for lethal pancreatic, brain cancers The Cancer Genome Atlas reports first results of comprehensive study of brain tumours Parsing the genome of a deadly brain tumor Studies spot numerous undiscovered gene alterations in pancreatic and brain cancers Massive cancer gene search finds potential new targets in brain tumors Collaboration between researchers yields more comprehensive portrait of brain cancer ......... ZenMaster

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