Detection of Mutations in Children with Brain Tumors

Uppsala University researchers have devised a novel approach for detecting mutations in pediatric brain cancers. They could also demonstrate that the mutations they discovered alter how cancer cells respond to cancer medication. These discoveries could lead to improved diagnosis and more tailored therapy for children with brain tumors. The findings were reported in the journal PNAS.

The most frequent malignant brain tumor in children is medulloblastoma. Although modern medicine has improved the prognosis such that over 70% of patients live more than five years, it often develops in the cerebellum, and not all patients can be treated. Cancer survivors who get intensive cancer therapy can experience serious side effects, including reduced balance and learning.

Much less is known about the remaining 97% of the human genome compared to the less than 2% of human DNA that gives birth to proteins. Thus, in a tumor-like medulloblastoma, 98% of the mutations take place in the less well-known region of the genome. There could be thousands of mutations, and it is challenging to distinguish between those important for cancer and those of little consequence.

The researchers employed a technique they recently created as part of an international partnership to obtain a thorough understanding of what mutations are significant in medulloblastoma. The method focuses on conserved regions of the genome and is based on the notion that DNA sequences that have stayed constant throughout the course of millions of years of evolution are likely to have significant roles.

In the new study, mutations in patients with medulloblastoma were compared with information about how well an individual position in the genome has been kept throughout evolution. Mutations in areas that hardly changed at all can be assumed to be most important.”

Ananya Roy, Study First Author and Researcher, Uppsala University

A total of 114 of the 200 000 mutations discovered in 145 individuals were located in regions of the genome that are known to be conserved. Even though some of these genes showed changed protein levels in medulloblastoma, several of these changes took place in genes that had not previously been identified to be mutated in this tumor.

The recently discovered mutations are found in DNA, which gives instructions on how much, when, and where proteins should be produced. Therefore, the findings could explain past reports of various protein levels in medulloblastoma.

We focused on mutations at the best-preserved positions, as these are likely the most critical ones for gene regulation. This way we can sort out the most important mutations, which would otherwise not be possible, and then test their functionality.”

Karin Forsberg-Nilsson, Study Lead and Researcher, Uppsala University

The mutations affected the gene expression in medulloblastoma cells in culture, and the researchers discovered distinct mutations in various age groups and subgroups of the disease.

This shows that our method works, and can provide a clearer picture of how these mutations regulate protein levels in cancer cells.”

Kerstin Lindblad-Toh, Study Lead, Uppsala University

The study also demonstrated how the new method’s mutations altered the resistance of the cancer cells to cancer drugs. As a result, this novel method of mutation analysis could recommend customized therapy.

This implies that a drug is chosen for a patient based on their unique mutation pattern, a practice that is becoming more and more common in the treatment of cancer.

But for this to work, there has to be a drug that is already on the market, may be used to treat another disease, and can be used to treat a small number of cancer patients who have the “right mutation”. The results of the new study may increase the number of mutations that could be treated, providing patients with more customized therapy in the long term.

Forsberg-Nilsson concluded, “To be able to use cancer mutation analysis for precision medicine, a lot of genetic information about each patient is needed. Since all children with brain tumors in Sweden are now offered whole genome sequencing analysis, i.e., the entire tumor genome is mapped, there are good possibilities to develop the analysis further to benefit patients.”