Precision brain cancer diagnosis

When doctors diagnose a brain tumor, they often face a high-stakes mystery: Is it slow-growing and treatable or aggressive and deadly?

In late 2024, doctors at MaineHealth faced this exact dilemma. A new patient, Roxanne Leet, was suspected to have a benign, slow-growing brain tumor called a meningioma based on initial scans. But when tissue from her tumor was sent for genomic analysis, the results predicted a different cancer type. Given the unexpected finding, the tumor was then sent to the JAX Advanced Precision Medicine Laboratory (APML) as part of a collaboration between MaineHealth and JAX. There, scientists examined the tumor’s DNA, RNA, and methylation—unique patterns of methyl chemical groups along strands of DNA that control gene activity.

JAX is one of only a handful of institutions in the United States that offer both next-generation sequencing and methylation testing for tumors, and the data they provided changed the patient’s diagnosis. The tumor was not a meningioma, but a sarcoma – an aggressive cancer rarely found in the brain. Instead of following up surgery with occasional brain scans, she now needed a regimen of radiation, with potential for future chemotherapy, and to undergo whole-body surveillance to ensure that the sarcoma had not spread elsewhere.

“Looking at the methylation alongside sequencing data is really helpful in trying to understand where a tumor originated and to clarify a diagnosis,” says Christine Lu-Emerson, a neuro-oncologist at MaineHealth. “This information not only lets us give patients a more accurate prognosis, but can guide our treatment as well.”

A cellular fingerprint

Every cell in your body carries the same DNA, but not every cell reads that DNA the same way. Methylation acts like highlighters, marking which genes turn “on” or “off” in different cells.

For instance, the cells found in the brain’s protective meninges use different genes than cells found in the brain’s connective tissues and blood vessels. So, although those cells contain identical sequences of DNA, they have methyl groups attached to different sections of that DNA.

In 2018, researchers in Germany discovered that looking at both genome sequencing and the methylation profiles of brain tumors, which are notoriously hard to categorize, could lead to much more accurate diagnoses than relying on previous methods.

In other words: methylation patterns in meningiomas – originating from the meninges – are very different from the methylation seen in sarcomas, which begin in connective tissues.

The JAX APML began offering methylation profiling to outside institutions in 2022 and has processed about two hundred tumor samples each year since. When a patient with brain cancer either undergoes a biopsy or has surgery to remove a tumor, a cluster of cancer cells are isolated and sent to the APML.

“JAX is really well-suited to be able to do this,” says Kelly. “We already had the equipment and expertise that not many labs in the country have.”

Qian Wu, a neuropathologist at UConn Health, is among those who collaborated with JAX to launch methylation profiling. She now sends about a quarter of all the new brain tumors samples she encounters to the APML for testing.

“With brain tumors, getting a biopsy at all is incredibly difficult and we sometimes only get a tiny amount of tissue that is really hard to work with,” explains Wu. “In the past, we put those cells under a microscope and tried to make a diagnosis based on how they looked. Methylation profiling gives us a lot more data with our limited samples and acts as an independent way of diagnosing brain tumors.”

Wu explains that DNA methylation analysis is considered the best method of diagnosing brain tumor severity. While she can identify a tumor’s type under a microscope, grading its aggressiveness (on a scale of 1 to 4) is much harder. Methylation analysis helps refine this grading process.

Methylation profiling across Maine

In September 2024, JAX launched a collaboration with Lu-Emerson and her colleagues at MaineHealth—facilitated through the Maine Cancer Genomics Initiative (MCGI)—to run a trial studying how methylation profiling could improve outcomes for brain cancer patients in Maine. As part of the trial, the APML now provides sequencing and methylation profiling for select brain cancers diagnosed at MaineHealth. After processing each sample, Kelly sits in on a tumor board meeting discussing the patient’s case with clinicians. 

“We’re all learning together and it’s been a really exciting project,” says Kelly. “We’ve had a number of cases where a tumor is initially thought to be one thing and it turns out completely differently.”

Through the collaboration, Kelly’s team at JAX is learning how to fine-tune their methylation profile analyses so they are most useful to clinicians, and the MaineHealth team is learning how to interpret the new types of data.

Lu-Emerson points out that with many other cancers, clinicians have become very good at subdividing tumors in different types. With breast cancer, for instance, patients are told whether they have a hormone-positive tumor or a triple-negative tumor. The cancer type dictates how the tumors are treated and how long a patient is expected to survive.

“With brain cancer, we haven’t had that kind of ability to differentiate tumors,” Lu-Emerson says. “It would be really nice if we could let the patients know from the beginning what we expect with their cancer type. Methylation profiling is paving the way for that.”

Ongoing research

Although already changing the course of treatment for some patients, brain tumor methylome profiling is still in its early days. Researchers need to continue collecting data on tumor methylomes to find new patterns associated with rarer cancer types and treatments.

A few months into the MaineHealth collaboration, 11 brain tumors have been analyzed at JAX and Kelly hopes to see those numbers grow in coming years.

Ultimately, clinicians hope that the technology gives patients more clarity, faster diagnoses, and potentially better treatments. That’s what scientists at JAX are working to deliver.

Learn More