As director of cancer genomics at NYU Langone Health’s Perlmutter Cancer Center, Marcin Imieliński, MD, PhD, combines medical training as a pathologist with extensive experience in the fields of computational biology and genomics. Dr. Imieliński, who joined Perlmutter Cancer Center in October 2022, also holds a joint appointment at the New York Genome Center as a core member.

Dr. Imieliński’s research focuses on cancer whole-genome sequencing, particularly in developing new algorithms for analyzing cancer whole genomes as well as developing new technologies to study the structure of cancer genomes.

He discussed technologies he has developed to analyze the vast amounts of data generated by whole-genome sequencing, the potential for incorporating these technologies into clinical care for people with cancer, and more.

Can you tell us a little about your background? Where were you before you joined Perlmutter Cancer Center?

I am an MD who is trained in pathology, which means that I have an interest and understanding of cancer biology and disease processes and diagnostics. I also have a deep background in computational genomics, developing algorithms and more recently assays. A common feature of a lot of the science that we do in clinical diagnostics is that it is very data rich, and genomic data, in particular, requires computational approaches. I was previously at Weill Cornell Medicine from 2015 until I joined Perlmutter Cancer Center last year to take on an exciting new initiative to expand NYU Langone’s clinical molecular testing to include whole-genome sequencing.

My training and longstanding interest has been in developing genetic biomarkers that can help us find out what therapies we can give to patients and which clinical trials we can enroll them in, taking advantage of all the technology developments in genomics to advance clinical cancer care.

What are some of the technologies that you developed to study cancer whole genomes?

We’ve been interested in what I think is still the most challenging aspect of the cancer genome, which is rearrangements and copy number alterations. These genetic changes don’t just create small typos in the DNA, which are easily detectable using standard clinical assays or standard algorithms, but much larger scale structural alterations that will move pieces of DNA from one part of the genome to the other, or duplicate them, or some combination of the two. There is a tremendous amount of complexity in some of the rearrangements that happen in cancer. It’s fascinating that these cancer cells can even survive with such deranged genomes, but it’s also very likely that many of these changes are driving cancer. There is already a lot known about that, but I still think there is a lot more to discover, particularly the interface of copy number alterations and rearrangements—how they essentially cooperate to alter genome structure—and how we can interpret that.

Currently, the state-of-the-art or the workhorse technology is a technique called short-read whole-genome sequencing, which involves breaking down the genome into smaller fragments and then sequencing these fragments. We have been developing algorithms that can work backwards from whole-genome sequencing data, where we have billions of short sequences, and use that to reconstruct the altered cancer whole genome. That allows us to infer patterns of DNA damage that might tell us whether certain repair pathways are broken, and it can help us identify new genetic changes that drive cancer or maybe even tell us what therapy it responds to. But the most interesting changes that the algorithms that we’ve developed can help us characterize are these alterations that both rearrange and amplify genomic sequences.

Another technology we are working on has been looking beyond just the sequence of these genomes, and looking at the way that these genomes fold in the nucleus. Genomes of normal cells are folded in a very characteristic way into the nucleus. Those patterns of folding are thought to drive normal cell development. But in cancer, where you have rearranged sequences, those sequences still have to fold into the nucleus. We have been developing new assays that help us understand that folding.

Another area that the lab is focusing on is developing newer technologies for long-read sequencing, which allows for the sequencing of much longer stretches of DNA compared to traditional short-read sequencing methods. We recently developed a new assay called Pore-C, which leverages this kind of long-read sequencing. We are scaling up Pore-C to look at large numbers of tumors and understand how these genomic rearrangements can perturb genome folding.

How can your research be applied to patient care?

Applying these technologies for the care of people with cancer is what brought me to NYU Langone. We have been developing many of these technologies to obtain a very detailed and mechanistic understanding of cancer genome evolution and particularly genome structure. With my clinical background and training, my mission has always been to apply my science to change clinical practice. For a long time it was really impractical to do whole-genome sequencing in the clinic, but that is what we need to get the resolution of the genome that we have been pursuing in the lab.

The cost of sequencing has been flat since about 2015, but very recently the key patents that have propped up the price of sequencing have begun to expire, and the cost has gone down about fivefold. That’s exciting because everything else in the world is getting so much more expensive, but this is one commodity that is getting cheaper and likely will become a lot cheaper. Some people think that the price of sequencing can go down maybe another 5- or 10-fold. We are going from a world where the cost of a genome sequence has been around $1,000, and if you want to do cancer genome sequencing, the cost has been about $3,000 to $4,000. We are on the cusp of an era where it will cost $100 to do the basic sequencing, and even a $10 whole genome may not be science fiction.

I think this is an exciting time when whole genomes could enter into the standard of practice. And I think it is inevitable. There are a lot of opportunities for us to change cancer care, including better matching of patients with therapy or more accurate diagnosis or prognosis. I think where the promise lies is in clinical trial enrollment, where we can use features that we can only identify in whole-genome sequencing to identify the patients that are most likely to respond to specific treatments. That will improve recruitment to certain trials and help us pursue certain therapies that are targeting specific variants, like structural variants or copy number alterations or other signals that we can only identify through whole-genome sequencing.

The other promise with whole-genome sequencing is it offers us the opportunity to detect cancer relapse at the earliest possible stage using a technology that has been pioneered by a former colleague of mine at Weill Cornell, Dr. Dan Landau. There are companies pursuing this, but I think this is something that we can also get started here at Perlmutter Cancer Center. The idea is once we have a whole-genome sequence of the primary tumor and the sequence of the patient’s tumor sample, we then have a full compendium of these mutations. Most of these mutations do not impact treatment; they are what we call passenger mutations. But each of those passenger mutations is a unique tattoo of that cancer’s genome.

If we see one instance of that mutation in the patient’s plasma, which we can get from a blood sample, that tells us that there is still residual cancer in that patient. This is really important for patients who have a tumor removed with surgery or radiation or have received chemotherapy, and we want to be able to track if that cancer has come back. I think one immediate or very near-term application of whole-genome sequencing will be to leverage this. The fact is that this kind of whole-genome sequencing of plasma DNA, in conjunction with the sequencing of a solid tumor, is the most sensitive way to detect cancer relapse. And I think we can probably detect it months before these tumors can be seen with imaging. That is a hypothesis that we are going to test, but I see that as one of the several routes that I think we can get this technology working for our patients here. And that will help us blaze a trail in what I think is going to be a sea change in the oncology field and in both industry and academia. In that way, NYU Langone can be at the forefront of this next era.

What do you think the time frame is for that?

I think the time is now. There are some logistical challenges, but I think that NYU Langone is well positioned. Dr. Matija Snuderl (associate professor in the Department of Pathology at NYU Grossman School of Medicine and director of molecular pathology at Perlmutter Cancer Center) recently received approval from the U.S. Food and Drug Administration (FDA) for a targeted sequencing test that involves the sequencing of both a tumor and a matched normal sample. That’s one of the essential pieces to getting a whole-genome sequencing cancer test working.

Many institutions do not have targeted sequencing incorporated into their molecular pathology workflow. I think that gives us a time advantage, and I think this is something that we can get up and running at some level within a year. Within five years, I want every patient at Perlmutter Cancer Center to get an upfront whole-genome sequencing test and then monitor for relapse with a blood test that uses whole-genome sequencing of their plasma. How frequent that test will be will depend on how advanced the tumor is, but I think that is something that I think within five years we should be able to offer. The key with any of these kinds of new technologies, whether they are therapies or new diagnostic modalities, is how we can make them pay for themselves.

With regard to your expertise, what do you bring to Perlmutter Cancer Center that strengthens its research portfolio?

Since I joined Perlmutter Cancer Center, I have been pleasantly surprised to find that there is a great deal of synergy between the existing strengths here and my expertise, particularly in the realm of genetics and genomics and understanding genome evolution. I’ve talked to Dr. Benjamin G. Neel (professor in the Department of Medicine at NYU Grossman School of Medicine and director of Perlmutter Cancer Center) about how happy I am to discover that, and he told me it’s not a coincidence. I think it is most likely a product of the vision that’s already in place here to recruit people who can find ways to work together.

I think there are many ways that my genomics and computational biology and molecular pathology expertise naturally connects with Perlmutter Cancer Center’s very strong programs in tumor immunology, in DNA repair, and in chromatin biology and 3D genome folding. In disease-specific biology, whether it is lung cancer, where I have done a lot of work, or in breast cancer or gynecological malignancies or melanoma, I have been really excited at all the unexpected research synergies that I have found here. I think there is a lot of room for building exciting new basic science programs that will leverage not just the methods that we have been developing, but some of the biological directions that I wish to pursue.

For example, we just published a paper online August 16 in Nature studying a DNA repair defect called homologous recombination deficiency, which affects patients who are born with a defective copy of the BRCA1 or BRCA2 gene. People with these gene defects are prone most commonly to breast and ovarian cancers, but more recently these genes are thought to play a role also in pancreatic and prostate cancers. This latest study uses genome analysis and long-read sequencing to identify new features that let us recognize the homologous recombination deficiency phenotype in whole genomes. It also suggests a new mechanism of DNA repair in tumors that lack BRCA1 or BRCA2 and different mechanisms for BRCA1 and BRCA2 deficiency.

This story is an example of a study that bridges both the clinical and basic research sides of my expertise extremely well. On the basic research side, I think the mechanistic implications here are potentially very deep, and there is tremendous strength at NYU Langone in understanding DNA repair mechanisms, particularly in homologous recombination deficiency. It will be great to explore collaborations there. And then on the clinical side, homologous recombination deficiency is an important aspect of breast, ovarian, prostate, and pancreatic cancers. There are strong clinical and translational research efforts in these directions here as well. I think this is just one vignette of how the ongoing work in my lab has a very natural and exciting synergy with the existing strengths at NYU Langone and at Perlmutter Cancer Center.