Lauren Gatta

A new study by researchers from Yale and the University of California, San Diego has revealed a previously unknown DNA modification in the glioblastoma tumor.

The researchers found consistently high levels of the DNA modification in glioblastoma tumor tissues, as compared to normal human central nervous system cells. These findings shed light on the notoriously lethal nature of glioblastomas, elucidating how these brain tumors manipulate cell processes that typically occur during early human development. The research was published in the journal Cell on Nov. 1.

“The glioblastoma is one of the most malignant tumors in humans,” said Andrew Xiao, co-corresponding author of the paper and genetics professor at the Yale School of Medicine. “The patient will usually die within three to six months. This study provides insight on the mechanisms behind why these tumor cells are so deadly.”

The recent paper extended prior 2016 findings on the same DNA modification, an epigenetic marker known as N6-methyladenine. The modification is normally present in embryonic stem cells — thus enabling the growth of a fetus — but disappears later in normal adults. The researchers found, however, that adult glioblastomas have a hundredfold increase in this DNA modification, indicating that the cancerous cells are hijacking operations involved in early cell growth that normal adult cells rarely utilize.

The team came to this conclusion by extracting DNA from the stem cells of patients suffering from glioblastomas. They then performed a dot blot analysis — a technique used to identify proteins — and discovered extremely elevated levels of the N6-methyladenine modification.

According to Ranjit Bindra ’98 GRD ’05 MED ’07, a professor of therapeutic radiology and experimental pathology at the School of Medicine, the significance of the study lies in its novel conclusions about N6-methyladenine and ALKBH1, the protein that regulates levels of this modification.

“The first takeaway for us as brain tumor doctors and researchers is how much more we have to learn about brain tumors and the glioma world as we know it,” said Bindra, who was not involved in the study.

Bindra mentioned that the protein ALKBH1 had previously been “elusive and poorly described,” with its relevance to cancer unclear. Yet this study emphasized ALKBH1’s importance to glioblastoma formation.

He added that there was one question open for further study: an understanding of how ALKBH1 was directly regulated in glioblastomas.

“The authors address it in the discussion [section],” Bindra said. “But a lot more work needs to be done to understand the link between ALKBH1 and N6-methyladenine.”

The next steps for this research, according to Xiao, are to find out how the DNA modification works in the tumor cells and to analyze its prevalence across the spectrum of human tumors. He emphasized the importance of investigating whether the modification was a common phenomena in all tumors or if it was just restricted to brain tumors.

As one of the biggest challenges when treating glioblastomas is their resistance to traditional cancer treatments. Xiao said that this research opens doors to opportunities for new drug developments — drugs that could work to inhibit this DNA modification.

“It will be a very effective way to improve the outcome of chemotherapy or radiation therapy,” Xiao said.

Bindra added that ALKBH1 enzymes could also serve as therapeutic targets for new cancer treatments. As for further research, he said, the team could investigate the specific role that N6-methyladenine plays in tumor formation and the consequences for different genes altered by this modification.

In 2015, 22,850 people were diagnosed with brain or other nervous system cancers in the United States, according to the National Cancer Institute.

Meera Shoaib | meera.shoaib@yale.edu

Freya Savla | freya.savla@yale.edu