A Children’s Hospital Los Angeles study has shed new light on the molecular drivers of FOXR2-activated CNS neuroblastoma, an extremely rare pediatric brain tumor that can be difficult to diagnose without advanced testing.
The study, led by Jessica Tsai, MD, PhD, and Jianling Ji, MD, MS, FACMG, identified specific genomic changes that turn on the oncogene FOXR2 in these tumors. The team also found a pattern of copy number changes that could help clinicians recognize this rare tumor.
The research was a collaborative effort between the Cancer and Blood Disease Institute and the Center for Personalized Medicine. Results were published in Neuro-Oncology Pediatrics.
“By identifying these different mechanisms of FOXR2 activation, we’re starting to build a clearer picture of how these tumors develop,” says Dr. Tsai, a pediatric oncologist at CHLA, which is home to one of the largest pediatric brain tumor centers in the country. “That not only helps with diagnosis, but it also gives us a foundation for future research into how to better treat them.”
Understanding FOXR2 activation
FOXR2 is an oncogene that is normally turned off in the brain but becomes activated in certain cancers. Dr. Tsai’s lab focuses on understanding this process in pediatric brain tumors and the role it plays in these cancers.
“FOXR2-activated CNS neuroblastoma tumors all have FOXR2 turned on, but how that happens hasn’t been fully clear,” says Dr. Tsai. “There are many different ways that FOXR2 can be activated that we didn’t fully appreciate before.”
To better understand these mechanisms, researchers used a combination of genomic sequencing and other molecular techniques to analyze tumor samples. They identified a range of structural changes—including insertions, inversions, and more complex rearrangements—that activate FOXR2.
“Many of these changes occur outside the gene’s coding region,” she explains. “That means they may not be detected by standard clinical testing.”
Clues for diagnosis
FOXR2-activated CNS neuroblastoma, which is distinct from traditional neuroblastoma, has only been recognized within the past decade. As the researchers evaluated clinical outcomes in their cohort, they found that most patients had initially been classified as having other tumor types—and all had been treated differently.
At CHLA, advanced molecular and genetic testing is routinely used to support diagnosis and guide care for pediatric brain tumors—a collaboration between the Center for Personalized Medicine, the Brain Tumor Center, and the Cancer and Blood Disease Institute.
Not all centers perform this testing, however. Without it, FOXR2-activated CNS neuroblastoma can be easily missed, Dr. Tsai notes.
In addition to the structural genomic changes, the researchers identified a recurring pattern of copy number alterations, including gains of chromosome 1q and losses in regions such as 16q and 11q. While not specific to this tumor, the pattern may serve as a useful signal when more advanced molecular profiling is not available.
“Copy number changes are things that many labs can already detect,” she says. “If clinicians start to see this pattern, it should prompt them to take a closer look and consider additional testing.”
Next steps
The team is now collaborating with international partners to combine data and build a comprehensive catalog of how FOXR2 is turned on across pediatric cancers.
“If we can bring together data from different institutions, we can start to better understand the molecular events driving these tumors and then model them in the lab,” Dr. Tsai says. “That information is critical for informing future research into how to better treat these cancers.”