Genetic drivers of deadly brain cancer uncovered

Scientists have uncovered a variety of genetic mutations that, in combination, can fuel the development of glioblastoma, which is an aggressive, hard-to-treat brain cancer.

What is more, the researchers identified two genetic mutations that drive chemoresistance in glioblastoma tumors, a finding that could lead to more personalized treatment strategies for the deadly brain cancer.

Study co-author Sidi Chen, of the Systems Biology Institute at Yale University in New Haven, CT, and colleagues recently reported their results in the journal Nature Neuroscience.

Also referred to as glioblastoma multiforme (GBM), glioblastoma is a deadly, fast-growing brain cancer that develops from astrocytes, a type of star-shaped glial cell that normally provides neuronal support.

According to the American Association of Neurological Surgeons, glioblastomas account for around 52 percent of all primary brain tumors, and they are most common among adults aged between 45 and 70.

When it comes to treating glioblastomas, surgery is often the first port of call, though it is rare that the entire tumor can be safely removed. As such, surgery is usually followed by radiotherapy and chemotherapy.

It is estimated that patients with aggressive glioblastomas who are treated with radiotherapy and temozolomide (a chemotherapy drug) have a median 5-year survival rate of around 10 percent.

Glioblastoma and gene mutations

While the precise cause of glioblastomas is unclear, researchers have previously identified hundreds of gene mutations that might be involved in the development of these tumors.

However, Chen and team say that it is possible that many of these gene mutations work together to form glioblastomas, but identifying which genes are involved in such collaborations has been challenging.

For their study, the researchers used CRISPR gene editing and a genetic screening technique to search for combinations of genetic mutations that might fuel glioblastoma formation in the brains of mice.

From an analysis of more than 1,500 genetic combinations in the mice, the researchers identified a number of genes, including B2m-Nf1, Mll3-Nf1, and Zc3h13-Rb1, that work together to cause glioblastomas.

Additionally, the team identified two gene mutations - Zc3h13 and Pten - that affect the gene expression of Rb1 mutations, which increases resistance to the chemotherapy drug temozolomide.

Findings may fuel personalized treatments

The team says that these findings could lead to more personalized therapies for patients with glioblastoma; they could help doctors to pinpoint which treatments are most likely to work based on the combinations of genetic mutations they possess.

What is more, the researchers say that their novel gene editing and screening technique could be used to identify combinations of genetic mutations that fuel the development of other cancer types.

"Taken together, our study provides a systematic and unbiased molecular landscape of functional tumor suppressors in an autochthonous mouse model of GBM, opening new paths for high-throughput analysis of cancer genetics directly in vivo."