Medulloblastoma patients whose tumors contain circular extrachromosomal DNA (ecDNA) are twice as likely to relapse and three times as likely to die within five years of diagnosis, according to new research. Medulloblastoma is an aggressive cancer most often seen in children.
“Medulloblastoma arises in the cerebellum, which is a delicate structure deep within the brain. This makes it difficult to remove the tumor completely without damaging surrounding brain tissue,” senior author Lukas Chavez, PhD, tells Inside Precision Medicine. “It’s also a heterogeneous group of tumors with different genetic and molecular characteristics. Making it difficult to develop a one-size-fits-all treatment approach,” he added. Chavez is a professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys.
To address these challenges, Chavez and his team compiled a database of 465 medulloblastoma patients using data that was publicly available and from patients diagnosed at Rady Children’s Hospital. Their analysis focused on ecDNA, which is found as loops outside of chromosomes, and is an important driver of oncogenic gene expression, evolution of drug resistance, and poor patient outcomes. Their findings were published in Nature Genetics.
“There are very few effective treatments available for medulloblastoma, and most treatments carry substantial risks of brain damage or secondary cancers,” says Chavez. “There is a critical need for new therapies that minimize unwanted side-effects. There is still so much we need to learn about what drives medulloblastoma at the molecular level, and this study is a step in the right direction.”
There are around 350 new medulloblastoma diagnoses per year in the U.S., and most of these are in children. This cancer often resists treatment, which involves a combination of surgery, radiation, and chemotherapy.
“Because medulloblastoma is rare, one of the challenges of studying the cancer is compiling enough patient data to study the disease holistically,” notes Chavez. “Fortunately, modern technology is now democratizing data science, which is transforming the way we study rare cancers.
“These ecDNA fragments are unique to cancer cells, and understanding how and why these DNA loops form and uncovering ways to therapeutically target them is a significant goal for researchers studying cancers of all types, not just medulloblastoma,” he adds.
The study revealed that while only 18% of the tumors had ecDNA, these patients were twice as likely to relapse and three times as likely to die within five years of their diagnosis.
“We’re finding that the presence of ecDNA fragments has a strong association with the clinical outcomes of medulloblastoma.” says Chavez.
The researchers then analyzed individual tumors, and found that even within a single tumor, there was large variety in how much and what kinds of ecDNA were present in individual cells.
“The genetic variety between different cells within the same tumor could help explain why medulloblastoma is so capable of evolving to resist treatment,” said Chavez. “While some tumor cells may be eliminated, others survive the treatment and continue to grow.”
The researchers hope that in the future, it will be possible to find new drugs that can interfere with the effects of ecDNA.
Chavez notes, “We have now received funding from the NIH for a research project over the next five years, with which we will test in preclinical studies what role ecDNA plays in the development of treatment resistance and whether we can prevent the emergence of ecDNA with new combination treatments and thus achieve an improved therapeutic outcome.”
