Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

The Cancer Genome Atlas exposes more secrets of lethal brain tumor

11.10.2013
Project delves deeply into genomics of 599 glioblastoma multiforme cases to better target disease

When The Cancer Genome Atlas launched its massively collaborative approach to organ-by-organ genomic analysis of cancers, the brain had both the benefit, and the challenge, of going first.

TCGA ganged up on glioblastoma multiforme (GBM), the most common and lethal of brain tumors, with more than 100 scientists from 14 institutions tracking down the genomic abnormalities that drive GBM.

Five years later, older and wiser, TCGA revisited glioblastoma, producing a broader, deeper picture of the drivers – and potential therapeutic targets – of the disease published in the Oct. 10 issue of Cell.

"The first paper in 2008 characterized glioblastoma in important new ways and illuminated the path for all TCGA organ studies that have followed," said senior author Lynda Chin, M.D., professor and chair of Genomic Medicine and scientific director of the Institute for Applied Cancer Science at The University of Texas MD Anderson Cancer Center.

"Our new study reflects major improvements in technology applied to many more tumor samples to more completely characterize the landscape of genomic alterations in glioblastoma," said Chin, who was also co-senior author of the first paper while she was on the faculty of Dana-Farber Cancer Institute in Boston.

"Information generated by this unbiased, data-driven analysis presents new opportunities to discover genomics-based biomarkers, understand disease mechanisms and generate new hypotheses to develop better, targeted therapies," Chin said.

About 23,000 new cases of GBM are predicted in the United States during 2013 and more than 14,000 people expected to die of the disease. Most patients die within 15 months of diagnosis.

Well of rich, detailed data will nurture better treatment

New information about genetic mutations, deletions and amplifications; gene expression and epigenetic regulation; structural changes due to chromosomal alterations, proteomic effects and the molecular networks that drive GBM make for a deep, broad dataset that will underpin research and clinical advances for years to come.

"Our main contribution is this tremendous resource for the GBM research community, which is already heavily relying on the earlier TCGA study," said co-lead author Roeland Verhaak, Ph.D., assistant professor of Bioinformatics and Computational Biology at MD Anderson. "Whatever new treatments people come up with for GBM, I'm very confident that their discovery and development will in some way have benefited from this rich and detailed data set," he said.

The Cell paper describes analysis of tumor samples and molecular data from 599 patients at 17 study sites. Detailed clinical information including treatment and survival was available for almost all cases.

New targetable mutations

In addition to confirming significantly mutated genes discovered earlier, such as the tumor suppressors TP53, PTEN and RB1 and the oncogene PIK3CA, the analysis identified 61 new mutated genes. The most frequent mutations occurred in from 1.7 to 9 percent of cases.

Two of these, BRAF and FGFR, might have more immediate clinical relevance, Verhaak noted. MD Anderson neuro-oncologists are checking to see if patients have these mutations. Drugs are available to address those variations now, Verhaak said. The BRAF point mutation in GBM is the same commonly found in melanoma, which is treated by a new class of drugs.

More twists and turns for EGFR

The larger data set and an improved analytical algorithm allowed major refinement of gene amplification and deletion information. For example, common amplification events were found to occur more frequently than previously known, including amplification of the epidermal growth factor receptor (EGFR) on chromosome 7.

EGFR is both amplified and mutated frequently in GBM; yet therapeutic efforts targeting EGFR so far have failed. "We found EGFR is more frequently altered than we already thought," Verhaak said.

Overall, the EGFR gene was mutated, rearranged, amplified or otherwise altered in 57 percent of tumors. Increased EGFR protein levels in GBM cells correlated with the many mechanisms of EGFR alteration, Verhaak said.

A treatment based on EGFR still has great potential, he noted. But strategies to target EGFR will need to address the likelihood that different alterations of EGFR might be present in the same tumor and affect the impact of targeted drugs.

Breaking GBM into molecular subtypes

Verhaak and other researchers in recent years have begun to classify GBM tumors by gene expression. Four such subgroups -- neural, proneural, mesenchymal and classical -- were further characterized by DNA methylation pattern, signaling pathway activity and by clinical measures such as survival and treatment response. Methylation of a gene turns it off.

Understanding the subgroups could establish biomarkers to guide treatment and identify new therapeutic targets.

The team found, for example, that the survival advantage of the proneural subtype depends on a specific DNA methylation pattern known as G-CIMP and that DNA methylation of the MGMT gene may serve as a biomarker of treatment response in the classical subtype.

Co-authors with Chin and Verhaak are 56 investigators from 39 institutions on behalf of the TCGA Research Network. MD Anderson co-authors are Siyuan Zheng, Ph.D., Rahulsimham Vegesna, and John Weinstein, M.D., Ph.D., of Bioinformatics and Computational Biology; W.K. Yung, M.D., of Neuro-Oncology; Kenneth Aldape, M.D., and Wei Zhang, Ph.D., of Pathology and Gordon Mills, M.D., Ph.D., of Systems Biology.

Zhang, Weinstein and Chin are all leaders or co-leaders of three of the seven TCGA Genome Analysis Centers.

Co-lead authors with Verhaak are Cameron Brennan, M.D., of Memorial Sloan-Kettering Cancer Center in New York and Aaron McKenna, Ph.D., of the Broad Institute of Harvard and MIT.

TCGA is a joint project of the National Cancer Institute and the National Human Genome Research Institute of the National Institutes of Health. This glioblastoma project was funded by NIH grants (U24CA143883, U24CA143858, U24CA143840, U24CA143799, U24CA143835, U24CA143845, U24CA143882, U24CA143867, U24CA143866, U24CA143848, U24CA144025, U24CA143843, U54HG003067, U54HG003079, U54HG003273, U24CA126599, U24CA126544, U24CA126546, U24CA126551, U24CA126554, U24CA126561, U24CA126563, U24CA143731, U24CA143843.)

About UT MD Anderson Cancer Center

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 41 comprehensive cancer centers designated by the National Cancer Institute. For 10 of the past 12 years, including 2013, MD Anderson has ranked No. 1 in cancer care in U.S. News & World Report's annual "Best Hospitals" survey. MD Anderson receives a cancer center support grant from the National Cancer Institute of the National Institutes of Health (P30 CA016672).

Get MD Anderson News Via RSS
Follow MD Anderson News on Twitter
Contact:
Scott Merville
External Communications
713-792-0611 office
713-515-4855 mobile
smerville@mdanderson.org

Scott Merville | EurekAlert!
Further information:
http://www.mdanderson.org

More articles from Health and Medicine:

nachricht A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital

nachricht Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

Im Focus: Quantum-physical Model System

Computer-assisted methods aid Heidelberg physicists in reproducing experiment with ultracold atoms

Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...

Im Focus: Glacier bacteria’s contribution to carbon cycling

Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.

A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

New quantum liquid crystals may play role in future of computers

21.04.2017 | Physics and Astronomy

A promising target for kidney fibrosis

21.04.2017 | Health and Medicine

Light rays from a supernova bent by the curvature of space-time around a galaxy

21.04.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>