Going beyond genetics yields clues to challenging childhood brain cancer

November 23, 2016, University of Michigan Health System
Representative confocal immunofluorescence images of human cerebellar tissues stained with antibodies against GFAP (green), H3K27me3 (red), and DAPI (blue) when the EGL is present before birth. Arrows indicate H3K27me3-negative nuclei in GFAP-positive radial glia. Arrowheads indicate radial glial processes. Dotted circles indicate granular cells. Solid lines indicate the pial surface, and the dotted lines indicate the extent of the EGL. Scale bars, 20 μm. Credit: J. Bayliss et al., Science Translational Medicine (2016)

Cancer is often seen as a disease of genetic changes. But one type of childhood brain tumor has stymied efforts to identify a recurring genetic defect.

Now, new research suggests changes at the epigenetic level - specifically alterations in proteins that affect gene expression, rather than - could be driving childhood ependymomas.

"Clearly there's more to cancer than just genetic mutations. Not every cancer is going to fit that box of having a genetic driver," says Sriram Venneti, M.D., Ph.D., assistant professor of pathology at the University of Michigan Medical School.

Three separate groups have performed advanced sequencing on ependymomas, a tumor that occurs at the part of the brain called the posterior fossa, which is the back base of the brain including the cerebellum, pons and brainstem. It can develop in both young and adults but is particularly challenging to treat in children.

When sequencing efforts did not yield any recurring genetic alterations, the University of Michigan-led team looked at epigenetics, in particular, changes in histone and DNA methylation, processes that regulate . They found about 80 percent of pediatric hindbrain ependymomas had substantially reduced levels of H3K27me3, a critical histone H3 protein modification. These tumor samples consistently tied to worse outcomes in children, suggesting a critical marker for predicting prognosis.

What's more, the researchers found that simple immunohistochemical staining methods in tumor biopsy samples can show whether the tumor has high or low levels of H3K27me3 that could predict prognosis.

"We could do it very simply, with a very fast and economic process that is easily incorporated in patient care," Venneti says. The study is published in Science Translational Medicine.

Traditional prognostic markers based on tumor grade have proven unreliable for ependymomas. Understanding a patient's prognosis can help doctors make treatment recommendations, which can be especially challenging for this disease in children.

In children, ependymomas typically occur under age 5. Surgery is a preferred treatment, but can be difficult in tiny brains where many critical functions are developing. Often, surgeons don't get the entire tumor out, leading to recurrence. Chemotherapy and radiation can cause devastating side effects to children, and it's not clear how beneficial the treatments are for this disease.

Researchers are also exploring a potential new therapy that could target H3K27me3 and reverse the lowered levels. This work is still in early phases; more study is needed.

Vulnerabilities in developing brain

Ependymomas also occur in adults, but in the study, none of the adult tumor samples had reduced H3K27me3.

On the other hand, Venneti's team found very similar epigenetic changes, including low H3K27me3 and similar DNA methylation, in another type of , diffuse intrinsic pontine gliomas or DIPG. These also occur in the posterior fossa of young children. Former U-M football coach Lloyd Carr's grandson, Chad Carr, died from DIPG in 2015.

"Different mechanisms are involved in these two tumors, but they arrive at the same place," Venneti says. "This suggests low methylation of H3K27me3 is important to tumors in this region of the brain. These tumors arise from similar epigenetic states."

Most childhood brain tumors develop in the posterior fossa of the brain - very different from where adult brain tumors occur. Venneti suggests that there may be something about the development of that region that makes children susceptible to these cancers. Preliminary research implicates neuronal stem cells. Studies looking at the posterior fossa of the developing human brain showed low H3K27me3. Neuronal stem cells are marked by their ability to differentiate into other types of cells. That process does not appear to happen in these .

"We still don't know the mechanism of how this is happening. Brain tumors are the most common type of solid cancer in children, but they're still poorly understood," Venneti says. "We hope that studying the epigenetics will give us more information on how the brain develops. And in turn, understanding how the develops could help bring answers to understand these deadly cancers."

Explore further: Single-cell analysis supports a role for cancer stem cells in brain tumor growth

More information: "Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas," Science Translational Medicine, stm.sciencemag.org/lookup/doi/ … scitranslmed.aah6904

Related Stories

Single-cell analysis supports a role for cancer stem cells in brain tumor growth

November 2, 2016
A study analyzing brain tumor genomics on a single-cell level has found evidence that cancer stem cells fuel the growth of oligodendrogliomas, a slow-growing but incurable form of brain cancer. In their paper receiving advance ...

For children with brain tumors, next-generation sequencing may lead to different diagnoses

November 16, 2016
Next-generation sequencing for patients at UCSF Medical Center is prompting changes in brain tumor diagnoses for some children and a retooling of treatment plans in many cases. Sequencing is also providing valuable insights ...

Promise of better targeted treatments now possible in children's brain cancer

October 27, 2016
More than 4,000 children and teens are diagnosed with brain cancer each year and the disease kills more children than any other cancer. Writing this week in the journal Cell Reports, researchers at Huntsman Cancer Institute ...

Biomarker may help predict aggressive cancers

November 5, 2013
For children with central nervous system cancers, the presence of a specific genetic modification—hypermethylation of the TERT promoter—may help predict tumor progression and patient survival, according to results presented ...

Brain cancer now leading childhood cancer killer

September 16, 2016
Brain cancer is now the deadliest childhood cancer in the U.S., now ahead of leukemia, a result of improved leukemia treatment and a frustrating lack of progress on brain cancer.

Brain tumors found to have a two-tier system

August 23, 2011
Ependymomas are the second most frequent type of malignant brain tumor in children. Ependymoma develops from precursor cells of the tissue that lines the hollow cavities of the brain. Therapy results of ependymoma vary immensely: ...

Recommended for you

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.