Neuro-oncology: An integrated approach to interpreting genetic information from brain tumor samples 


As part of Mayo Clinic’s Neuro-Oncology practice, the Division of Laboratory Genetics and Genomics tests about 50 brain tumors a week, and upwards of 1,500 brain tumors a year from all over the world. One of the most innovative and integrated in its field, this laboratory conjoins two main disciplines: cytogenetics and molecular genetics. Test samples from clients seeking answers are first accessioned by Mayo Clinic Laboratories, one of the largest reference labs in the country, before being sent to a specialty area such as genetics and genomics.

“Because our practice is distributed across all of these disciplines, we see different kinds of tumors, including many rarer tumors,” says Robert Jenkins, M.D., Ph.D., a consultant in Mayo Clinic’s Division of Laboratory Genetics and Genomics, and a professor of individualized medicine research. “So we have a lot of experience. Our current database has molecular information on over 5,500 patients. It’s a tremendous resource because we can access our prior experience.”  

Over recent years, the neuropathologic diagnosis of brain tumors has become more complex and more time-consuming. Why? Neuropathologists have discerned new tumors with similar histologic features or similar patterns of genetic alterations, including mutations and copy number alterations. At the same time, many tumors are getting more comprehensive genetic testing on a research and clinical basis. Furthermore, the latest edition of the WHO Classification of Tumors of the Central Nervous System (CNS), released in 2021, introduced major changes to the role of molecular diagnostics in the classification of CNS tumors. 

This means the level of expertise in the interpretation of genetic information from brain tumor samples is more critical to patient care now than ever before. “The 2021 WHO edition doesn't change how we do things; however, in some ways, the new guidelines make our work more complicated,” says Dr. Jenkins. 

Cutting-edge expertise supported by integration  

The practice’s most comprehensive genetic tests include the neuro-oncology NGS panel (Mayo ID: NONCP), which identifies mutations, gene fusions, and transcript variants associated with brain tumors, and the chromosomal microarray (Mayo ID: CMAPT), which evaluates copy number changes in tumor samples. Both tests help determine the diagnosis and/or prognosis for brain tumor patients.

Cristiane Ida, M.D., is a molecular neuropathologist and co-director of Mayo Clinic’s Molecular Technology Laboratory within the Division of Laboratory Genetics and Genomics. “I think our integrated approach is what makes us unique,” she says. “Brain tumor patients start their care with the neuro-oncology, neuroradiology, and the neurosurgery team. They perform the procedures and decide treatment. The Neuropathology group is the group that we typically work very closely with, because they give the initial assessment of the patient sample — is it a tumor or not a tumor? If it’s a tumor, what type of tumor? And based on that, they are the ones who are ordering the genetic tests from us. 

“But for us, it's not as simple as getting the patient sample, putting it in a machine, and getting the results in a report,” says Dr. Ida. “It's a complex, integrated, multistep workflow testing process with multiple teams involved. The process ends with a test report that integrates the provided neuropathological impression with the genetic test results.” 

When a Mayo Clinic Laboratories client, such as a pathologist or clinician, receives a genetic test result, they receive more than just a list of genetic alterations. “If you only tell pathologists and clinicians that this tumor has an X, Y, or Z mutation, they may not appreciate what those alterations mean,” says Dr. Jenkins. “Our clients need to know how the results fit in the context of the pathology and the other molecular tests. That is perhaps the most important part of the service we offer.” 

For in-house patient cases that come through the neuropathology practice, a multidisciplinary team comes together for a “molecular integration” meeting, wherein pathologists and geneticists discuss case findings. “The pathologists share what they are seeing, what they’re thinking,” says Dr. Ida. “We look at the genetic testing results. Then, as a team, we use WHO’s 2021 classification system to diagnose each brain tumor case.

"We put them into different ‘buckets,’ and these different buckets are highly associated with specific clinical outcomes, how the tumor will behave over time. We put everything together into a report that dictates and helps our neurology colleagues decide what treatment strategies are best for these patients.”

Amber Pryzbylski, a genetic counselor who works with the neuro-oncology group, chimes in: “What's really nice about our service is the integrated component. It’s that whole picture — what we’re seeing on a larger chromosomal level, and then also at the smaller DNA level, which can help give a more specific diagnosis for a patient.

“When the pathologist examines slides of a tumor sample under a microscope, they can look at what's going on in the cells and get an idea of which kind of tumor they think it is. Do they think it's an astrocytoma versus an oligodendroglioma? And then the molecular testing component can kind of lock that in place because, otherwise, the diagnoses can still be a little fluid. So, certain findings in the DNA, or lack of those findings in the DNA, helps push the diagnosis in one direction or another to confirm, or change it. It can also change the prognosis for the patient.”

New tests, new discoveries 

Before the team analyzes data from genetic testing results, they first make sure those test results are valid, have passed quality metrics, and that the data is reliable. Only then does the group proceed with evaluating the findings. And in the Division of Laboratory Genetics and Genomics, they don’t just evaluate tests, they design them. 

“We have the ability to actually design and decide what we are going to do,” says Dr. Ida. “And I think that's the other area of expertise that really sets us apart.”  

Dr. Jenkins’ group has also helped refine the neuro-oncology practice and genetic testing, including test offerings that have been recommended in the new WHO 2021 edition of CNS tumor classification. 

Meanwhile, his lab continues to make discoveries via collaborative clinical, translational, and basic science studies. For example, Dr. Jenkins recently co-led a study, featured in the journal Science, which found that a specific germline alteration (rs55705857) developed brain tumors more frequently, and much faster, compared to subjects without this alteration. The finding, relevant to other forms of cancers, may lead to new therapies that specifically target this DNA alteration.      

Sharing knowledge to expand expertise

The number of still undiscovered mutations and alterations behind brain tumors is nearly endless, which is why it’s critical for the group to continue their work.

“We are still in the precision diagnostic phase in neuro-oncology, meaning that, with the genetic testing and molecular biomarkers that we test for, we are helping to refine and define the diagnosis of brain tumors,” says Dr. Ida. “Once you start defining what the specific molecular markers are for tumors, then you can start looking at ways to target these specific markers and develop, hopefully, more efficient targeted therapies.”

Dr. Jenkins summarizes the practice this way: “Every day, we are determining how patients will be managed, because the management depends upon the pathologic diagnosis and upon the genetic results. Usually, we're providing extra information that helps refine the final diagnosis and how the patient should be managed. While it doesn't happen very often, sometimes the genetic tests completely change the diagnosis. It happened this morning with a case. In short, our work always puts the needs of the patient first.”

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Chris Bahnsen

Chris J. Bahnsen covers emerging research and discovery for Mayo Clinic Laboratories. His writing has also appeared in The New York Times, Los Angeles Times, and Smithsonian Air & Space. He divides his time between Southern California and Northwest Ohio.