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Oct 23, 2024, 11:13

Exploring the Future of Genomic Testing: Interview with John Herriges on Optical Genome Mapping

John Herriges is the Assistant Director of the Cytogenetics Laboratory and Associate Program Director of the Genetics and Genomics Fellowship at the Children’s Mercy Hospital. He holds a PhD from the University of Wisconsin and completed fellowships in Laboratory Genetics and Genomics at Children’s Mercy Kansas City and Clinical Cytogenetics at the University of Utah Medical Center. Dr. Herriges is board certified in both Laboratory Genetics and Genomics and Clinical Cytogenetics.

In this interview with OncoDaily, John Herriges, a specialist in genetics and genomics, shares his insights about the importance of OGM as a comprehensive technique that can detect structural rearrangements throughout the genome while providing detailed information down to the gene level.

What are some of the most significant advancements in genomic testing technologies over the past few years?

In the cancer realm I think that OGM, which has really come to everyone’s attention the last few years, has the potential to be a real gamechanger as it can help streamline testing for patients and can lead to a better genetic classification of tumors. There are a lot of other testing advances though that are significant, like long read sequencing, tumor methylation profiling, and RNA sequencing.

What types of genomic data analysis techniques are most commonly used in your work, and how do they contribute to patient outcomes?

Historically in our cytogenetics lab we have been using microarray, fluorescence in situ hybridization (FISH), and chromosome analysis (karyotyping) as our primary genetic tests. In the cancer realm FISH and chromosome analysis have been the gold standard test for genetic categorization of leukemias/tumors, with our findings helping to define tumor categorization, risk stratification, and treatment plans. Two prime examples are in certain leukemias we will look for rearrangements that result in BCR::ABL1 fusion and PML::RARA fusion.

Finding these rearrangements in a patient helps to define the leukemia the patient has, and both rearrangements have targeted therapies that typically lead to better patient outcomes. Microarray is a newer technology that is higher resolution and looks at genome wide copy number analysis. It can identify copy number changes that are prognostically or diagnostically significant and could be missed by chromosomes and FISH.

Can you explain what Optical Genome Mapping (OGM) is and how it differs from traditional genetic tests like FISH and karyotyping?

OGM is a technique that is run on very long strands of DNA from either tumor or germline samples. We fluorescently labeled these DNA strands at a specific sequence and then image them. These images are then compiled into a consensus map that essentially looks like a barcode for each chromosome. The patient’s map is compared to a normal map of the genome to see if there are any differences. So, for example in one case you could see that part of the map that typically aligns with chromosome 9 in a normal individual is aligning with chromosome 22, and this would be suggestive of a translocation between chromosome 9 and 22.

You could also see that your map for chromosome 9 is shorter or longer and this would be consistent with a deletion or duplication, respectively. All of this is done on at least the gene level, so in addition to knowing that the translocation between 9 and 22 has occurred you would also know what genes it is breaking in. In the cancer realm this is very important for diagnostic/prognostic purposes because these rearrangements will often lead to specific gene fusions that will help diagnose a specific disease and help the clinician decide how to treat the patient.

Karyotyping (chromosomes) is great at identifying coarse rearrangements throughout the genome but will miss smaller changes. FISH is great at identifying very small structural rearrangements, but is very targeted, so if you aren’t targeting the right region of the genome, you may miss the key finding. Microarray is genome wide and can look at copy number gains/losses down to the gene level but cannot detect structural rearrangements.

OGM is sort of like a combination of all three of these techniques in that it can detect structural rearrangements throughout the genome and can look at gains/losses down to the gene level. Also, unlike FISH it is not a targeted assay, so it is more amenable to identify novel or rare rearrangements that you typically wouldn’t think to look for.

Could you share more about the validation process you went through with? What were some key findings that stood out to your team?

We looked at over 60 samples that had been previously tested by traditional cytogenetic techniques (chromosomes, FISH, microarray) and ran them on OGM. We then blindly reviewed the results on OGM and compared them to the traditional test results. One major finding was that OGM identified all the major findings identified by traditional testing methodologies that would have impacted therapy. This was important because it meant that we could feel confident that it wouldn’t miss anything that traditional testing would find.

Another major finding was that it helped to further characterize the abnormalities that traditional testing had found. For example, when we do testing on leukemias we will often use FISH probes that look for rearrangement of a gene. If its positive we know that the gene is rearranged, but we don’t know the partner gene.

Knowing the partner gene can impact treatment/prognosis, and OGM was able to identify the partner genes in all rearrangement cases. Lastly, although the validation was not designed to identify novel rearrangements, we did identify two cases with rearrangements that helped to further classify the tumors and were not previously known.

How does the integration of OGM into clinical workflows affect the collaboration between geneticists, oncologists, and other specialists at Children’s Mercy?

I don’t think that this is going to have a huge affect on collaboration between our different providers from a clinical standpoint, but it will streamline what those providers need to order and review. From a research prospective OGM will identify novel rearrangements that we may have missed in the past, which we will want to collaborate on to publish so that the more providers know about these rare rearrangements.

Could you share some of your personal experiences working with OGM? What have been some key moments or insights that stand out to you?

To me the biggest “aha moment” was when we worked on a case during the validation that had a rearrangement that we had hypothesized involved ABL1, but OGM showed us that it involved JAK2 instead. The JAK2 rearrangement was something that we could have detected by FISH, but we didn’t look for it because the specific type of leukemia that patient had doesn’t typically involve JAK2.

When we did a literature search we did identify one other patient with the same type of leukemia who had the same rearrangement, and the authors of that paper hypothesized that this rearrangement could respond to a specific type of therapy that targets JAK2 rearrangement.

This was a key moment for me because it showed how OGM could find novel rearrangements that we wouldn’t typically think to look for and could miss with traditional testing methodologies. Although these types of findings may be rare they could have significant impacts on treatment for the patients that have them.

What areas of research are you most excited about in relation to OGM and pediatric genetics?

To me the biggest potential of OGM will be identifying novel fusions that could be missed by traditional cytogenetic testing methodologies. In some instances, it could mean that a patient could have their therapy altered because we identified a rare rearrangement that we typically wouldn’t think to look for. In others, the identification of a novel fusion may not have an immediate impact, but with time and more patients they could impact future patient’s care.

Also, on the germline side of things I think OGM has the potential to help look for answers in cases that have already been tested by traditional testing methodologies. OGM is great at looking at balanced rearrangements at the gene level and this is one area where traditional germline testing methodologies struggle.

Can you discuss any early feedback or results you’ve seen since implementing OGM? How have they influenced patient outcomes so far?

Right now, it is a little too early to tell about larger impacts on outcomes, but since we started running these clinically our results have been used to adjust therapy for at least one individual.

What is your long-term vision for OGM at Children’s Mercy? How do you see it evolving in the coming years?

My vision is for OGM to be done on all cancer patient’s seen at CMH. Right now, the focus is on leukemias, but ultimately, I would like to expand it into solid tumors because gene fusions are also very important in those as well.