“Not all heroes wear capes. Some wear coats – lab coats.” With these words, Methylation Man embarked on a series of epic diagnostic quests in The Pathologist in 2024, cracking brain tumor classification conundrums with the power of DNA methylation profiling.
As with any great comic strip, naturally we are curious about the man behind the superhero. We caught up with Matija Snuderl, MD, Director of Molecular Pathology at NYU Langone Health, to learn more about the tools in Methylation Man’s utility belt.
What inspired the creation of Methylation Man?
Brain tumors are among the most malignant tumors in the human body. Many of our patients are children with brain cancer, and we often find ourselves in the position of delivering the most difficult news to patients and parents.
Because DNA methylation profiling helps oncologists refine the diagnoses of brain tumors, it can help patients greatly; but it’s also a bit of an enigma. If I tell my patients that I’m going to examine the methylation profile of their DNA, they don’t know what that means. The same goes for many neurosurgeons and oncologists, who might have learned about the concept in medical school and not thought about it since.
So, we are often in the situation of explaining a complex concept over and over and trying to find the right language. I started to think about the best way to explain what we do. I’ve given a lot of educational and scientific talks, but I felt that a different approach was needed.
I’m based in New York, which, as we know, is where all the superheroes come from. I came up with the idea that DNA methylation profiling needed its own superhero to champion the technique, explain it simply, and show how it helps doctors to solve diagnostic conundrums.
What is the aim of the comic strips?
One of the aims is to provide easily digestible information on a complex condition for patients and their families. Few of them have any concept of the intricacies of tumor diagnostics, and often find the medical lingo used in discussions of blood tests, imaging, and molecular testing overwhelming.
But the testing is really critical because it defines their disease management, so we wanted the comic strips to help explain what’s involved, and how it helps us establish the best care.
The other aim is to help raise awareness of brain tumors. Because they are uncommon, there is little awareness of how difficult they are to treat. We wanted to give our patient advocates and fundraising partners a tool to help them easily explain the important diagnostic work that we do.
What is the role of DNA methylation profiling in advancing tumor classification?
DNA methylation can be regarded as a fingerprint of a cancer cell that contains information on where the cell came from it and how it became cancerous.
While all our cells contain the same genes, they all serve different functions in the body: tissue, organs, bones, and so on. So what makes brain cells look and function in a different way to, say, heart cells?
Well, DNA methylation – a type of epigenetic modification – shuts down some parts of the genome that the particular cell doesn’t need. All the cells have the same DNA code, but with different epigenetic modifications that determine their function.
This epigenetic fingerprint tells us about a cancer cell’s origins and the specific DNA mutations that are driving the tumor growth. That is really useful for the classification of cancers.
How are technologies such as nextgeneration sequencing and AI analytics driving expansion of DNA methylation applications?
The most common method of analyzing DNA methylation is using methylation arrays. Imagine a tiny tray of microscopic beads, each with a fragment of DNA from a tumor attached. Each fragment shows a different color signal according to whether it binds to the methylated or unmethylated tag. A sensitive camera then reads the color signal for every position in the human genome, from which a map of the methylation patterns can be determined.
Next-generation sequencing is also used for DNA methylation profiling. And new technologies are on the horizon, which will allow even greater sophistication.
Now let’s consider how we analyze the information. Methylation arrays might compare more than 900,000 sites across the genome, which generates a huge amount of data. We use a variety of computational approaches – best described as machine learning or AI – to process the data.
For every class of a tumor, we try to identify a distinct DNA methylation signature. We then use that signature to train our machine learning algorithm to identify each tumor type from its epigenetic fingerprint. After testing the algorithm, we develop a workflow through which it can analyze and classify unknown tumors for our patients.
AI-enabled DNA methylation tumor classification, along with next-generation sequencing, is now expanding applications beyond the central nervous system. Some examples are sarcomas, hematological malignancies, and kidney tumors.
What is being done to improve patient access to DNA methylation profiling?
We want to avoid the situation where DNA methylation profiling is only available to patients who are able to travel to a specialist cancer center. My goal has always been to make this technique accessible as a regular laboratory assay that can be set up anywhere and reimbursed by insurance. This was important, because we can’t afford to limit applications to the handful of sites that have access to philanthropic funding.
My team has spent a lot of time developing protocols that can be deployed in any lab with the relevant technology. We also share validation protocols so other teams don’t have to reinvent the wheel, enabling a “plug and play” approach on both the laboratory and computational side.
Of course, the data interpretation does require specialist knowledge of both the disease and the DNA methylation signatures. However, AI speeds up this process and opens up a test that is incredibly powerful in the hands of an experienced pathologist who can interpret the results in context. I always say that AI will not replace pathologists or physicians, but those who use AI will replace those who do not use it.
What’s next for Methylation Man? What are some of the problems he still needs to solve?
There’s still so much more we need to discover with DNA methylation. There’s a hint in a couple of episodes of the comic that DNA methylation is applicable to more than just brain tumors. There are other cancers that will really strongly benefit from DNA methylation classification.
My other dream is discovering how we can translate DNA methylation signatures into therapeutic discovery. We spent 10 years trying to better classify tumors for diagnosis and showed we can avoid more than 15 percent of misdiagnosis and diagnostic errors using DNA methylation. My hope is that, in the next 10 years, we can analyze this trove of data we collected and really focus on finding new therapeutic targets.
Perhaps one day Methylation Man will not only predict what’s going to happen with a patient, but perhaps change the outcome with a better therapy.
And, of course, after comic strips there is always a movie, right?
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