Gene sequencing project identifies potential drug targets in common childhood brain tumor
Researchers studying the genetic roots of the most common malignant childhood brain tumor have discovered missteps in three of the four subtypes of the cancer that involve genes already targeted for drug development.
The most significant gene alterations are linked to subtypes of medulloblastoma that currently have the best and worst prognosis. They were among 41 genes associated for the first time to medulloblastoma by the St. Jude Children's Research Hospital Washington University Pediatric Cancer Genome Project.
"This study provides new direction for understanding what drives these tumors and uncovers totally unexpected new drug targets. There are drugs already in development against these targets aimed at treating adult cancers and other diseases," said Richard Gilbertson, M.D., Ph.D., St. Jude Comprehensive Cancer Center director. Gilbertson and Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology, are the study's corresponding authors. The work appears in the June 20 advance online issue of the scientific journal Nature.
The results mark progress toward more targeted therapies against medulloblastoma and other cancers. While better use of existing drugs and improved supportive care have helped push long-term survival rates for childhood cancer to about 80 percent, drug development efforts have largely stalled for more than two decades, particularly against pediatric brain tumors.
"This study is a great example of the way whole-genome sequencing of cancer patients allows us to dig deep into the biology of certain tumors and catch a glimpse of their Achilles heel," said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. "These results help us better understand the disease and, as a result, we will be able to more effectively diagnose and treat these kids."
This study involved sequencing the complete normal and cancer genomes of 37 young patients with medulloblastoma, making it the largest such effort to date involving the cancer. Researchers then checked tumors from an additional 56 patients for the same alterations. The genome is the complete set of instructions needed for human life. It is carried in the DNA found in nearly every cell.
The findings are part of the Pediatric Cancer Genome Project, which launched in 2010 as a three-year effort to decipher the complete normal and tumor genomes of 600 young cancer patients with some of the most challenging tumors. The endeavor has already yielded important clues into the origin, spread and treatment response in childhood cancers of the blood, brain, eye and nervous system.
Medulloblastoma is diagnosed in about 400 U.S. children and adolescents annually. Their outcome varies widely based on the subtype they have. While nearly all patients with the wingless (WNT) subtype survive, just 60 percent of those with subtype 3 medulloblastoma are alive three years after diagnosis. WNT medulloblastoma is named for the pathway disrupted in the tumor subtype.
This study found a high percentage of patients with WNT-subtype medulloblastoma had mutations in the DDX3X gene. The investigators found evidence that mutated DDX3X is required to sustain the brain cells where WNT subtype tumors develop. The research also found evidence linking alterations in other genes, including CDH1 and PIK3CA, to the development and spread of the WNT subtype. "It is particularly exciting that these genes, or the pathways in which they work, are already the focus of drug development efforts. This opens up the possibility of using these drugs to treat medulloblastoma in new ways," said Giles Robinson, M.D., St. Jude Department of Oncology research associate and one of the study's first authors.
Investigators demonstrated that subtype three and four medulloblastoma often had alterations in genes that impact cell maturation. The genes carry instructions for proteins that add or remove the chemical group methyl to the H3K27 protein. H3K27 is part of the chromatin structure that packages DNA to fit inside cells. That packaging helps determine if genes are switched on or off. The addition of methyl to H3K27 permits less specialized cells to keep dividing and blocks activity of genes that would prompt cells to stop dividing, differentiate and take on more specialized roles.
Some subgroup 3 and 4 tumors were characterized by a gain in EZH2, which adds methyl to H3K27. EZH2 is also associated with adult cancers and the focus of ongoing drug development. St. Jude has begun screening those and other compounds for evidence of effectiveness against medulloblastoma.
In other subtype 3 and 4 tumors a different gene, KDM6A, was inactivated by mutations. KDM6A works to remove methyl groups from H3K27, thus eliminating this gene's function could keep cells in an immature dividing state. The results suggest the genes possibly work together to promote medulloblastoma development.
The EZH2 and KDM6A alterations were found only in the subgroup three and four tumors, which also had higher levels of H3K27 methylation than other medulloblastoma subtypes. "With this research we have 'lifted the lid' on the most aggressive and challenging form of medulloblastoma, subtype 3, which was really a black box in terms of our understanding, and revealed a major driver of the disease," Gilbertson said.
The findings add to mounting evidence from the Pediatric Cancer Genome Project that epigenetic changes play a pivotal role in fueling childhood cancer. Epigenetic mechanisms can serve as on-off switches, altering gene activity without changing the makeup of the gene. Such changes can lead to the unlimited cell growth of cancer.
Journal reference: Nature
Provided by St. Jude Children's Research Hospital
- Different origins discovered for medulloblastoma tumor subtypes Dec 08, 2010 | not rated yet | 0
- Genome code cracked for most common form of pediatric brain cancer Dec 16, 2010 | not rated yet | 0
- Cancer sequencing project identifies potential approaches to combat aggressive leukemia Jan 11, 2012 | not rated yet | 0
- Gene identified as a new target for treatment of aggressive childhood eye tumor Jan 11, 2012 | not rated yet | 0
- A divide and conquer strategy for childhood brain cancer Nov 22, 2010 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
Marie Curie's leukemia
May 13, 2013 Does anyone know what might be the cause of Marie Curie's cancer
- More from Physics Forums - Medical Sciences
More news stories
In a new study described in the journal Oncogene, researchers reveal how a key player in cell growth, immunity and the inflammatory response can be transformed into a primary contributor to tumor growth.
Cancer 4 hours ago | not rated yet | 0 |
A new study conducted using extensive medical records of over one million Israeli adolescents before military service shows clearly how exposure to the Israeli sun of young, light-skinned children increases substantially ...
Cancer 6 hours ago | not rated yet | 0
A new measure of the heterogeneity – the variety of genetic mutations – of cells within a tumor appears to predict treatment outcomes of patients with the most common type of head and neck cancer. In the May 20 issue ...
Cancer 10 hours ago | not rated yet | 0
Researchers at Mayo Clinic have developed a promising method to distinguish between pancreatic cancer and chronic pancreatitis—two disorders that are difficult to tell apart. A molecular marker obtained from pancreatic ...
Cancer 11 hours ago | not rated yet | 0
The use of a smartphone application significantly improves patients' preparation for a colonoscopy, according to new research presented today at Digestive Disease Week (DDW). The preparation process, which begins days in ...
Cancer May 19, 2013 | not rated yet | 0
New research suggests that for some hospitalized ICU patients on mechanical ventilators, using headphones to listen to their favorite types of music could lower anxiety and reduce their need for sedative medications.
4 minutes ago | not rated yet | 0 |
A small, easily implantable device called the Lung Volume Reduction Coil (LVRC) may play a key role in the treatment of two types of emphysema, according to a study conducted in Europe. Results of the study indicate the beneficial ...
4 minutes ago | not rated yet | 0
The early (within 24 hours of intensive care unit [ICU] admission) provision of intravenous nutrition among critically ill patients with contraindications (a condition that makes a particular procedure potentially inadvisable) ...
4 minutes ago | not rated yet | 0
Having a nighttime critical care physician in the ICU doesn't improve patient outcomes, research finds
With little evidence to guide them, many hospital intensive care units (ICUs) have been employing critical care physicians at night with the notion it would improve patients' outcomes. However, new results from a one-year ...
4 minutes ago | not rated yet | 0
(HealthDay)—Vitamin D supplements may help those with Crohn's disease overcome the fatigue and decreased muscle strength associated with the inflammatory bowel disease, according to new research.
14 minutes ago | not rated yet | 0