Alterations in ALK / ROS1 / NTRK / MET Drive a Group of Infantile Hemispheric Gliomas

An exciting new study out of the Hospital for Sick Children in Toronto has made some important findings about a poorly understood, high-risk cancer. Gliomas are rare brain tumors that can affect individuals of all ages. While studies are plentiful on pediatric and adult gliomas, infant cases are historically understudied – an unfortunate fact, considering central nervous system tumors are most common (and deadly) in this age group.

Dr. Cynthia Hawkins, a pediatric neuropathologist and one of the authors behind the study, has been researching pediatric brain tumors for over 20 years. She tells us this lack of data is due to both the rarity of infantile glioma (her hospital might see a case once every couple of years), and the fact that infants are less likely to be enrolled in clinical trials.

Hawkins and her team sought to account for this missing data. They wanted to shed light on the genetic root of the disease – the specific mutations driving tumor development in affected infants. In order to accomplish this, they needed to draw on colleagues from around the world. They reached out to fellow oncologists who’d treated infant gliomas in the past 30 years, requesting two things: tumor biopsies, and any relevant follow-up information about the patient – treatments they’d undergone, whether they’d relapsed, overall survival time, etc. The team’s goal was to determine whether there was an association between the tumors’ genetic profile and patient outcome.

We asked Hawkins about some of the biggest obstacles she and her team encountered in conducting such an ambitious study. She says they faced two major hurdles. The first, not surprisingly, was actually collecting the samples. “There was a lot of follow-up and making sure that people were maintaining their interest and continuing to send us the data that we needed.” However, she says the fact that they were able to compile the amount of data they did speaks to the interconnectedness of this research community. “The pediatric brain tumor world is small, and people tend to be very collaborative.”

The second challenge? Cytogenetically analyzing some less-than-ideal tissue. Because the samples they received were collected between 1986 and 2017, a fair number had significantly degraded DNA. “Because we’re looking at tissue that wasn’t necessarily stored for the purpose of research, often it wasn’t frozen tissue, which you’d ideally like to do genetic analysis on.” For the newest samples, they used RNA sequencing, which Hawkins says was the most robust, because it gives you a snapshot of the patient’s whole genome. But for samples that weren’t frozen or were more than a couple years old, the team used a combination of FISH, NGS, and nanostring technology, designing their own targeted panels to detect the presence of specific gene abnormalities. They ended up narrowing in on a few receptor tyrosine kinase (RTK) and RAS/MAPK pathway genes, which they found most frequently rearranged in the samples.

Results verified that tumor genetics were, in fact, tightly correlated with clinical outcome. They found that tumors could be divided into three categories : (1) hemispheric RTK-driven tumors (including ALK, ROS1, NTRK, and MET fusions) with an intermediate clinical outcome, (2) hemispheric RAS/MAPK-driven tumors with excellent long-term survival and minimal clinical intervention post-surgery, and (3) midline RAS/MAPK-driven tumors which have a relatively poor outcome even after conventional chemotherapy.

Importantly, many of the samples harbored a single gene fusion, which, when present, occurred at very high frequencies within the subtype - evidence that infant gliomas are single-driver tumors that likely require just one mutation to initiate tumorigenesis. Hawkins says this points to an age-specific mechanism unique to infant cancers. “It suggests that if you acquire one of these fusions early on, in the right cell context, there may be cell populations around in early childhood that are susceptible to being transformed by a single alteration.”

So what does this mean from a treatment perspective? Hawkins says it’s a promising sign that we might be able to use the same gene-specific inhibitors used on adults to treat infants, who might actually fare better with targeted therapy. “For adult cancers that are genetically more complicated, it’s less likely that a single targeted agent will be sufficient treatment. For pediatric cancers, however, many respond very well to single targeted agents, and don’t tend to develop resistance to these agents at the same rate as in adult cancers.”

Hawkins is determined to bring this research to the forefront of the pediatric oncology community. She and her team have already presented their research at several conferences, and recently spoke in front of a national neurooncology board about their findings. “A big part now is making everyone aware that these alterations are present at a very high rate in affected babies, that there are drugs available to treat these alterations, and getting the support of the drug companies to run trials that include infants.”

This publication is currently available in Nature Communications: