�An array of broken, missing, and overactive genes -- some implicated for the showtime time -- have been identified in a transmitted survey of glioblastoma, the most common and lethal form of adult mastermind cancer, report scientists from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, together with their collaborating investigators at 18 institutions and organizations.
The large-scale combing of the brain cancer genome confirms the key roles of some previously known mutated genes and implicates a mixture of other genetic changes that may be targets for future therapies.
The findings, posted online by Nature on Thursday, Sept. 4, help solidify and expand the "parts list" of genetic flaws linked to glioblastoma multiforme (GBM). Lynda Chin, MD, at Dana-Farber and Harvard Medical School (HMS) and Matthew Meyerson, MD, PhD, at Dana-Farber, HMS, and Broad, co-led the writing effort for the starting time summary of data from the $100 million pilot project of The Cancer Genome Atlas (TCGA), funded by the National Institutes of Health (NIH). The data are released to the public at TCGA's website as they ar generated.
Systematic multidimensional genomic studies of patient samples of glioblastoma began in 2006 as the first TCGA program. The pilot is designed to determine the feasibility of a full-scale effort to systematically explore the universe of discourse of genomic changes mired in all types of human cancer and to demonstrate the values of such efforts in forward cancer research and improving patient care.
The current paper in Nature summarizes the interim analyses of data gathered in the GBM pilot study. "The findings of pregnant mutations in genes that have implications for healing development exemplify precisely how unbiased and systematic genus Cancer genome analyses can tether to paradigm-shifting discoveries," aforesaid Chin, world Health Organization chairs the GBM disease working group within TCGA.
An exciting instance, Chin aforesaid, is an unanticipated observation of a link between DNA methylation of specific genes and DNA vivify defects, leading to a hypothesis around a voltage mechanism of resistance to a common chemotherapy drug used for brain cancer.
The Nature paper complements a parallel cogitation by Johns Hopkins researchers of 22 GBM tumors, which was also published on Sept. 4 in the journal Science.
"These information show that this glide slope, of looking at at turgid numbers of tumors and a magnanimous number of genetic factors, can be done and the results are actually valuable," said Meyerson. "We have made significant novel findings, and the reproducibility of the data is high."
Collaborating teams analyzed 206 specimens of glioblastoma tissue donated by patients at four medical centers. Their approach was "multidimensional" -- looking for several categories of flaws simultaneously.
These included mutations -- "typos" in the DNA code of a cistron that alters its function; too many or too few copies of a given factor; damage to chromosomes causation loss or dislocation of pieces; factor activity that is higher or glower than normal; and changes in DNA methylation -- turning genes on or off without affecting their structure.
The researchers also had access to information on how the patients wHO donated the samples had fared, including how they responded to certain drugs.
Automated machines at three Genome Sequencing Centers, including the Broad Institute center lED by Eric S. Lander, Broad Institute director, were set to work reading material the DNA messages in the cancer cells' nuclei. Of the roughly 20,000 protein-coding genes in the tumour cells, 601 genes were selected by the GBM disease working group for detailed sequencing -- determinative the parliamentary law of chemical "letters" in the DNA -- and comparison. A second instalment of genes is already being sequenced, and Chin and her group are working on additional factor lists for mutational analyses.
Five major factor mutations have previously been identified in glioblastoma cells; the new sequencing sweat revealed three that hadn't been discovered. One mutation affects the NF1 factor, which causes neurofibromatosis. A second genetic mutation is in the ERBB2 gene known to be involved in breast malignant neoplastic disease. The third affects a gene in the PIK3 signaling pathway that is abnormally excited in a number of cancers, just this fussy gene, PIK3R1, had been only seldom implicated in any cancer. "Each of these mutated genes defines a new target for glioblastoma treatment," said Meyerson.
As they examined the data, the researchers found that three signal pathways -- networks of genes and proteins that act together to run out a cellular function -- were disrupted in more than three-quarters of the GBM tumors. They are known as the cyclin-dependent kinase/retinoblastoma pathway that regulates cell division; the p53 tumor suppressor footpath, which is involved in response to DNA impairment and cubicle death; and the receptor tyrosine kinase pathway that carries signals that control cell growth.
Chin said that the most exciting finding is that this multipronged study design also enabled the scientists to take a potentially important connection between a methylation alteration in the glioblastoma cells and which drugs should be ill-used for discourse. Brain tumors that contain a methylated, or silenced, form of a cistron known as MGMT are known to be more susceptible to cancer drug temozolomide (Temodar). Therefore, Temodar is routinely given along with radiation to patients with MGMT methylation.
But the analysis of methylation in the glioblastoma tumors, when matched with the patients' medical history, revealed a cautionary sign. When such patients were treated with Temodar and subsequently had a return of the tumor, it was very likely to become resistant to treatment because of "hypermutation" -- an increased rate of gene changes that light-emitting diode to the tumor's power to skirt the drugs.
"This could throw immediate clinical applications," said Chin.
The discoveries in the paper are only the tip of an expected iceberg, aforesaid the authors. The "about powerful wallop" is expected to issue forth from further research studies carried extinct by scientists who make use of the data released freely by TCGA, they said.
More than 21,000 new cases of brain cancer are expected to be diagnosed in the United States this year, and more than 13,000 people ar likely to die from the disease.
"These impressive results from TCGA provide the most comprehensive view to date of the complicated genomic landscape of this deadly malignant neoplastic disease," said NIH Director Elias A. Zerhouni, M.D. "The more we learn nigh the molecular basis of glioblastoma multiforme, the more swiftly we can develop better ways of portion patients with this awful disease. Clearly, we should move onwards and put on the power of large-scale, genomic research to many other types of cancer."
Chin is co-principal investigator of a TCGA center with Raju Kucherlapati of HMS, and Meyerson is head teacher investigator of a TCGA Cancer Genome Characterization Center at the Broad Institute. Chin is the scientific director of the Belfer Cancer Genomics Center in the Center for Applied Cancer Science at Dana-Farber, and Meyerson directs the Center for Cancer Genome Discovery at Dana-Farber.
The research was funded by grants from the NIH.
Dana-Farber Cancer Institute (hypertext transfer protocol://www.dana-farber.org/) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and precaution centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
The Broad Institute of MIT and Harvard was founded in 2003 to bring the mogul of genomics to biomedicine. It pursues this mission by empowering creative scientists to ct new and robust tools for genomic medicine, to make them accessible to the global scientific community, and to apply them to the understanding and discussion of disease. The Institute is a research coaction that involves faculty, professional staff and students from throughout the MIT and Harvard academic and medical communities. It is conjointly governed by the deuce universities. Organized around Scientific Programs and Scientific Platforms, the unique structure of the Broad Institute enables scientists to collaborate on transformative projects across many scientific and medical disciplines. For farther information around the Broad Institute, go to http://www.broad.mit.edu/.
Source: Bill Schaller
Dana-Farber Cancer Institute
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Tuesday, 9 September 2008
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