Going Beyond Genetics Yields Clues to Challenging Childhood Brain Cancer


 

Types and Locations of Paediatric Brain Tumours

Types and Locations of Paediatric Brain Tumours

Cancer is often seen as a disease of genetic changes. But one type of childhood brain tumour 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 genetic mutations — 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 tumour 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 children 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 gene expression. They found about 80% of paediatric hindbrain ependymomas had substantially reduced levels of H3K27me3, a critical histone H3 protein modification. These tumour 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 tumour biopsy samples can show whether the tumour 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 tumour 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 tumour 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 tumour 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 paediatric brain tumour, 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 tumours, but they arrive at the same place,” Venneti says. “This suggests low methylation of H3K27me3 is important to tumour s in this region of the brain. These tumours arise from similar epigenetic states.”

Most childhood brain tumours develop in the posterior fossa of the brain — very different from where adult brain tumours 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 brain tumour s.

We still don’t know the mechanism of how this is happening. Brain tumour s 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 brain develops could help bring answers to understand these deadly cancers.

 

Story Source: University of Michigan Health System

 

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About LFCT

This is a blog about CHILDHOOD CANCER and CHILDHOOD CANCER AWARENESS Little Fighters Cancer Trust is a non-profit organisation that offers support and aid to Children with Cancer and their families. When a child is diagnosed with cancer it affects the whole family. One of the parents, usually the mother, must give up their job to care for the child and this creates financial problems for the family. In South Africa especially the majority of these families are not well-to-do; many of them are rural. A diagnosis of cancer can wipe out any family’s finances, let alone a poor family. The costs of special medications, special diets, hospital stays, transport to and from the hospital or clinic and accommodation and food costs for the mother who spends most of the time at her child’s bedside are astronomical. These are the people and problems that fall through the cracks, and these are the people that Little Fighters Cancer Trust has pledged to help in any way possible. LFCT takes a holistic approach to assisting the Children with Cancer and their Families, with the main aim to be the preservation of individual dignity and pride. Little Fighters Cancer Trust also focuses on promotion and advocacy of National Childhood Cancer Awareness in an effort to increase awareness of Early Warning Signs of Childhood Cancer. This would result in earlier diagnosis, giving the Child with Cancer more of a chance at Treatment and Survival. See "About" for more Background info

Posted on 14 December, 2016, in Blog, Research. Bookmark the permalink. Leave a comment.

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