Leukemia Genetics and Biomarkers

Participants:     Dr. Lucy Godley, Northwestern Medicine

Savina Chacheva, Cancer Wellness Center

Lindsey Whyte, Leukemia Research Foundation

 

- Thank you everyone for joining us today. This is Leukemia Research Foundation's new – sorry- Leukemia Genetics and Biomarkers webinar, which is co-hosted today by Cancer Wellness Center. We're joined by Dr. Lucy Godley from Northwestern Medicine in Chicago, who will share information about genetics and biomarkers, what they are, how they can guide leukemia and MDS treatment. She'll also respond to questions that have been submitted previously or are submitted during the session.

 

My name is Lindsey Whyte and I'm the Director of Programs & Partnerships at the Leukemia Research Foundation. The Foundation's mission is to cure leukemia by funding innovative research and supporting patients and families. The Foundation has raised over $90 million in support of our mission since our founding in 1946, and we've funded research grants to over 750 investigators worldwide during that time. Our support programs for leukemia patients and their loved ones include information and resources, education programs like today's, financial assistance and a directory of other helpful organizations and resources on our website. I'd like to take a moment to thank our webinar partner Cancer Wellness Center and with us today is Savina Chacheva who will say a few words about her organization and how they support cancer patients.

 

- Thank you. Thank you so much Lindsey, and as always, we are so grateful for our continued partnership with the Leukemia Research Foundation. Hello everyone. My name is Savina Chacheva. I'm the Program Director at the Cancer Wellness Center. As Lindsey said, I'm really glad that you can all join us today. For those of you who are joining for the first time, I would like to share a little bit more about the Center. The Center was founded in 1989 as a nonprofit organization with the mission to help anyone touched by cancer find a way forward. Each year, our free counseling services, support groups, health and nutrition programs serve over 2000 community members of all ages and backgrounds. People with cancer, family members, friends and caregivers all come to us to connect and cope. Our services, which are both virtual and in person, include education programs like the one today that aim to help you navigate the very challenges that come with living with a cancer diagnosis, wellness classes like yoga, meditation, nutrition and more that provide a holistic approach to healthy living. And support services, including counseling for individuals, families, couples, children, and those bereaved as well as support groups that are designed to help our participants manage the emotional and mental impact by cancer. If you would like to learn more about the center and connect to our free programs and services, please visit cancerwellness.org and the link will be included in the chat. Thank you so much Lindsey.

 

- Thank you. Yes, and we will be sending an email after this, after the end of this session today, and that will also have the link to Cancer Wellness Center as well. So just a few quick housekeeping items for the program today. All participants will be muted throughout the program. If you already submitted a question, please know that we have your questions. We did receive quite a few, so we'll do the best we can to go through all the questions. We did group some, so we'll kind of cover some by topic area, and you can also type a question into the Q & A box at the bottom of the zoom screen. We can't promise that we'll get through everything, but we'll do the best we can. As I said, after today's program, we'll be sending a brief evaluation through the email and that'll also have the link to a Cancer Wellness Center in it. And it's going to have some information about another webinar that's coming next week. So please keep an eye out in your inbox for that email as well.

 

Okay. So we're grateful today to have Dr. Lucy Godley from Northwestern Medicine who integrates her research with the clinical care of patients with blood cancers, generally. Dr. Godley received scientific training at Yale, Harvard and UC San Francisco and medical training at Northwestern. After training in internal medicine and hematology oncology at the University of Chicago she held a long time faculty position at the University of Chicago and then relocated in May of 2023 to Northwestern University where she is the Jeffrey and Maryanne Silver Family Professor of Oncology, Director of the Silver Family Blood Cancer Institute and Clinical Director of Cancer Genetics for the Robert H Lurie Comprehensive Cancer Center and Division of Hematology Oncology. Dr. Godley also runs an independent research laboratory focused on understanding the molecular pathways that drive hematopoietic malignancies, especially how germline predisposition alleles contribute to individual and family risk. Dr. Godley has contributed to the recognition of germline DDX41 ETV6 and CSF3R variants as risk factors to developing hematopoietic malignancies. And she is also studying how deleterious germline RUNX1, CHEK2 and BRCA1/2 variants drive these cancers, especially considering how the development of clonal hematopoiesis and inflammatory pathways contribute to tumorigenesis. Dr. Godley- That was mouthful- Dr. Godley has shown the germline contribution to hematopoetic malignancies occurs throughout the entire age range of life and is more common than previously anticipated, which has important implications for the allogeneic hematopoietic stem cell donor pool. Dr. Godley practices bench to bedside medicine that advances patient care through a deep appreciation of the latest scientific findings. I'm really grateful that she's joining us today. Dr. Godley, please take it away.

 

- Thanks so much Lindsey. I really want to thank you and the Leukemia Research Foundation and Cancer Wellness Program for having me here today. And to all of you who are listening and for sending your questions in advance, it was really helpful to me to see what your questions were so I can try to address them during the talk. So I'm going to share my slides, hopefully you can see them. We'll go to slideshow, so hopefully they show up now.

 

- Yes, we see them.

 

- Okay, perfect. So here on just this first slide, I have my email address and my office phone number in case at the end you still have questions and we don't get to all the questions, but feel free to email me or give me a call. I'm happy to take your questions.

 

So we're going to talk about the blood cancers focusing on leukemia, but really what I'm going to say today is applicable to all of the blood cancers. And yes, they are genetic, meaning that a lot of times people have inherited a DNA change that puts them at risk. We're going to talk about that today. I just wanted to start with some really basic slides to bring us all on the same page, what we mean by the bone marrow, what looks healthy, what looks problematic, and hopefully a lot of this at the beginning is review for you. So the bone marrow is the soft inner part of the bones. It's present in almost all the bones of your body and this is where all your blood cells are produced. This is the factory of your blood cells. On the left here you see the healthy bone marrow. You can see that there are bony, we call these bony spicules. This is like the bone that's kind of creeping into the inner part of the soft part of the bone. So there's bone in the bone marrow. This white stuff are globules of fat, so there's a lot of fat in the bone marrow. And then you can see all this blue stuff. These are cells. So when you look at a healthy bone marrow, it looks kind of spotty. It has the fat globules in it, it has the bone in it, and then it has the cells. You can see that looks pretty different from this diseased bone marrow that I show you on the right. There's no fat anymore, it's just solid cells and they're pretty much all the same. So the variety of cell production is decreased and that on the right is what we see when we have involvement of the bone marrow with a bone marrow cancer.

 

Here on the left on this slide, you can kind of see a picture of the bone. We all think of, you know, the hard outer part of the bone, but what we're talking about in the bone marrow is this inner softer part and we have the blood cells are derived from this mother stem cell called the hematopoietic stem cell or blood stem cell. And that mother stem cell gives rise to all of the progeny cells. So we have this kind of array of all these different cell types that can be made from this mother stem cell. All of these neutrophils, basophils, eosinophils, these are all different types of white blood cells. We have the red blood cells that carry the oxygen around to the tissue. Then we have these platelets. These are little cell fragments that are out in our blood and help the blood to clot. And when we have a blood cancer, one of these cells kind of goes out of control and it starts growing uncontrollably. And as you saw from the previous slide, it pretty much takes over the bone marrow.

 

Now the blood cancers can be divided into different categories. The largest categories we call leukemias, lymphomas, which are cancers of the lymphoid cells, the B cells or the T cells. And then a special type of cancer from the most mature type of B cell is called multiple myeloma. Within the leukemias we have different kinds. We have acute, those are medical emergencies, they come up very suddenly or we can have chronic leukemias. Those develop more slowly. And then we divide by the type of cell, either the myeloid cell, these are usually white cells that are fighting infection or the lymphoid cells, the B cells or the T cells, those are designed to fight viral infections. So depending on what kind of blood cancer you have, you fall into one of these different categories. And within leukemia we either say acute myeloid, acute lymphoid, chronic myeloid or chronic lymphoid. Those are all the different types.

 

So I believe that all cancer arises as a combination of inherited risk and environmental insult or environmental exposure. And families share both the DNA, they share their inherited risk and they live together, they share environment. So cancer arises in families as a consequence both of genetics and environment. Now whether a particular tumor is more inherited, genetic driven, or it's more environmentally driven, is a very individual kind of situation. I think we have to understand cancer- this really is true for all cancers, not just the blood cancers- at many different levels to really be able to develop strategy to treat it.

 

We start with the baseline DNA we were born with. Those are our baseline genetics. And those, the DNA sequence that you're born with, sets out risk for a disease in your lifetime. And so what I have focused on for the past you know more than 10 years of my professional career has been understanding the DNA changes that people are born with that already give them a cancer risk. Then over time we develop DNA changes in all of our body's stem cells. We have stem cells in all of the organs of our body. It's most easy to measure that in the blood system because our mother stem cells put those progeny cells out into the peripheral blood and mix them all around. So if we sequence the peripheral blood, we're looking at the state of all the active stem cells, there's no other organ in the body where we can do that. So blood is very, very unique. And what we can do if we sequence people's blood who are out there living their lives perfectly healthy, we already see that they have step one, step two, or maybe even step three of developing a leukemia. Those are what we call the acquired genetics or the acquired DNA changes that have happened during someone's lifetime in the mother stem cells. And we give a special name to that process now that's called clonal hematopoiesis. And then layered on top of that, we have additional DNA changes that happen over more time that actually give you the actual cancer cell.

 

So you can see that cancer is a layered risk starting with what you're born with, the DNA changes you're born with and then DNA changes that happen over your lifetime and then even layered on top of that in your life to give you an overt blood cancer. We also know from science right now, although this hasn't really gotten to the clinic yet, that the organisms that live on your skin and in your gut, all the bacteria and other microorganisms are contributing to your cancer risk. They affect your immune system. And the immune system is extremely important in monitoring cancer throughout your body. And I believe that we have the capacity to understand the three layers here that I put in the blue. We have all the techniques to do that right now. We will very soon be analyzing the microbiome, the bacteria and other organisms that live within your body and on the surface of your body. And really we put all of that together to give a very personalized treatment plan for each person.

 

So we're going to start talking about the germline or the inherited DNA changes. And I'm not going to go into too much detail here at all except to say that some inherited changes in these genes all the way to the left give rise to those myeloid cancers. Others of them give rise to lymphoid cancer or immunodeficiency problems with the immune system where the immune system isn't as strong as normally, and then other risk to either myeloid or lymphoid. And these genes here all the way to the right give risk for either myeloid, lymphoid or even solid tumors. Now there's kind of a riddle in English that says, how much does a ton of feathers weigh? And you're kind of giving the answer, right? A ton of feathers weighs a ton. The idea there is that each feather is very, very light, but if you have a lot of feathers, you get something heavy. Well, in the same way, each of these disorders may be relatively rare, but there are so many different genes that we have to think about and inherited risk becomes something very common. And you can see that I've put some of these feathers in larger size here at the bottom just to make the point that bone marrow failure conditions are comprised of many, many, many genes. So you can see that if we're trying to do comprehensive testing for someone, we have to cover a lot of DNA because there are many, many genes that are involved. And every month or so, another gene gets added to the list. So I advocate for testing that really covers your entire DNA to be sure that we're comprehensive for finding inherited cancer risk.

 

Now when we talk about blood cancers, we come across certain cellular pathways very, very commonly. And one of the most important pathways that we have for cancer risk, blood cancer risk, is in DNA repair. It's really important that your DNA is intact, right? If your mother stem cell is trying to make those baby cells, she has to copy her DNA and put the DNA into the baby cells. And if that copying process doesn't work correctly and our pathways to fix DNA mistakes or DNA damage is not good, those DNA changes are perpetuated into the daughter cells. And then again, you have that layered effect of the risk.

 

So as we look at inherited risk, we come across this pathway again and again and again, especially here in Chicago. And so when you have DNA damage, this protein ATM is recognizing that DNA damage and it talks to this protein called CHEK2 and CHEK2 talks to P53 and BRCA 1 and BRCA 2. And all of these can have inherited risk. If you have an inherited DNA change in any one of these genes, you have inherited cancer risk. A lot of you already know about BRCA1 and BRCA2 because those are kind of known in the lay community as being risk factors for breast and ovarian cancer. But as I hope to show you later, we think there are very strong risk factors in the bone marrow as well. We even had some questions that some of you submitted about CHEK2. So you're already very aware of CHEK2. And CHEK2, if I were to point my finger at the number one gene in Chicago, it's CHEK2. And why do I make this point about "in Chicago"? Because actually what we see is just dependent on our population and the United States is the melting pot, right? The United States people come from all different parts of the world. Here in Chicago we have a very large Polish influence, a Polish ancestry and ancestry from Eastern Europe. So we see DNA changes here in Chicago that represent that population. If you go to the west coast, they don't see so much CHEK2 because their immigrant population is much more from Asia for example. So what we see here in Chicago is very reminiscent of the influence of immigration into Chicago and that's very influenced from Poland and Eastern Europe.

 

So here I show you on the left a representative family tree of what one of these families looks like. This is actually the first family that we diagnosed with inherited change in CHEK2. And this red arrow points to patient number one. She actually was first diagnosed with a blood cancer when she was 35 years old, but that blood cancer myelodysplastic syndrome is usually diagnosed in much older people like around 75. So why is she getting an old person's disease when she's only 35 years old? And she was very curious about that. She's actually a physician and she found out that we do this kind of testing and she came to us in Chicago and she said, I want to know why I am so young with an older person's disease. And we found out she had the inherited CHEK2. And so she decided to have a transplant. And after her transplant for the MDS, that part was all fixed because she got healthy stem cells, but she had that CHEK2 in all the cells of her body. And she knew that the CHEK2 gave a risk for the solid tumors. So she had extra screening for breast cancer, she actually had a small breast cancer in her left breast, she had bilateral mastectomy. She went on to have extra screening for thyroid cancer. She had a small thyroid cancer. And so this does feel a bit like whack-a-mole and not to scare any of you, but when you have these inherited DNA changes, they're in all the cells of your body and multiple organs are at risk.

 

And so we need to be very comprehensive in our cancer screening. But when we do that, we can save lives multiple times over and that's how she considers us to have saved her life three times over. You can see that her brother shares the CHEK2, he's been healthy so far. Her mom died of multiple myeloma that lymphoid malignancy I was telling you about. She has an uncle who died of a B-cell lymphoma, another B-cell malignancy. And you can see a great aunt here with breast cancer. So again, CHEK2 is a mix of myeloid, lymphoid and solid.

 

Here on the right you can see just the distribution of the different CHEK2 changes that we see in our cohort here from Chicago. And you see this buildup of so many people with this one change called the I200T or sometimes we call it I157T. Half of our families have exactly the same change. It's very, very common in the Polish population. And if you talk to a breast cancer doctor, they tell you this is a weak cancer risk. Well it doesn't seem weak to me when I see people with blood cancers and half of them have the same change. So we got really curious about CHEK2 way back in the day and we thought maybe the CHEK2 is kind of stronger in the bone marrow than it is in the breast. And we set out to test that. Here's one way that we tested it and I'm not going to go through all the numbers in a lot of detail, but we just said, well if we are Poland, if we're pure Poland in Chicago, are we just seeing what you would expect from 5% of the population having this change? The answer's no. That's here in this thing called an odds ratio. So this being five where the number is much, much higher than one. And so it's the, we call this the confidence interval, is between three and nine or you know on average five, this is positive meaning this is real. So that means that we see people with this change, the I200T or the I157T more than you would expect if, than if we were just pure Poland. And this one, the S428F, this variant is common in the Ashkenazi Jewish population. So we ask the same question, if we were all Ashkenazi Jewish in Chicago, is this what you would just find? And the answer's no. Actually the confidence interval and the odds ratio are even higher for this change. So it's even a higher risk for the blood cancers if you have this change than the general population. But interestingly, this CHEK2 change the Del1100C, which is very strongly associated with breast cancer. It's not so strong to be associated with blood cancers. You can see the confidence interval crosses one, the P-value is not significant. So this really suggests that not all CHEK2 changes are the same for each organ. These two, the I200T or the S428F, they're really strong in the bone marrow, whereas this 1100 Del variant is stronger in the breast.

 

So depending on which change you have, different organs can be more or less at risk for cancer. I think that's a really important point. And here we're just showing you the distribution of the different kinds of tumors that we see in our patients here on the left, myeloid, lymphoid, myeloma, solid tumors. It doesn't matter if those tumors like the blood cancers come before a solid tumor or after a solid tumor. All of these kinds of tumors are seen just like I showed you from the family tree.

 

And then on the right I show you data from the United Kingdom. The United Kingdom has done a pretty amazing experiment scientifically. They've sequenced half a million people and they've connected to that DNA sequence to all their medical records. So we know all the people who are participating and it's called the UK Biobank, out of half a million people who've been sequenced, we know everybody with the CHEK2 and we can look at their medical records and we can see that sometimes they get a leukemia before a solid tumor and sometimes they get a leukemia after a solid tumor, which we call a therapy related leukemia. And we've done a lot of statistics and I'm going to share those with you that really argue that CHEK2 is a direct cause of these blood cancers. And I'm happy to say you can see that down here that just got accepted for publication last week.

 

Here are the ages at which these tumors present. You can see the age starts as young adults in the twenties and is like a straight line all the way up into the eighties. So it doesn't matter what age you are, you are at risk for cancer with CHEK2. And as Lindsey kind of said in the introduction, that's kind of a theme in our work that cancer risk is a risk throughout the entire age range of life. It's not like any one age is particularly at risk. We did look to see if there was any kind of signal in the leukemias, in the myeloid leukemias that developed. Could you guess who might have a CHEK2 change? And these are these biomarkers that we'll talk about at the end, but there really was not a signal from any particular gene except there was a signal in the chromosomes.

 

So probably a lot of you know that when the myeloid leukemia or any kind of leukemia is diagnosed, we characterize the DNA changes in that leukemia and if the chromosomes are normal and what we see in people who have the CHEK2 changes, they're more likely to have rearrangements of the chromosome, and that makes sense because you might remember from that figure that I showed right at the beginning, the CHEK2 pathway represents double strand DNA breaks. And so, if the DNA is broken, one chromosome's broken, the other chromosome is broken, it's more likely that this cell, which is not so good at recognizing those breaks, puts two chromosomes together that shouldn't be put together. So we do see a chromosome signature in these leukemias. These are some of the calculations that we did that said, okay, you have a CHEK2 inherited change. Is it like a guarantee that you're going to get cancer? What's the frequency? And a little bit is taken from some of the clinical reports right now that call the CHEK2 changes weak cancer risks. Well, if you have a problematic change in CHEK2, that's the red line here. Your lifetime risk of developing cancer is just under 30%, one out of three. So you can decide if that's weak or not. For me, if you told me I had a 30% chance in my whole life of getting cancer, I would not consider that weak. So I'm hoping that once, whoops, sorry, I'm hoping that once these data get published, which was just last week, but once they really come out, clinical labs will stop calling CHEK2 changes- weak cancer changes -because, one out of three, I do not think it's weak.

 

Now you can see the penetrance or the likelihood of developing a blood cancer is only 2%. So you might consider that weak, but that's because blood cancers are rare cancers, it's much more likely that you would get a solid tumor. So these are just some of the numbers that we have. I'm happy to talk about those in more detail at the end. We did more of those odds ratio kind of calculations to say from the UK biobank, okay you have a problematic change in CHEK2, are you statistically more likely to get a blood cancer or myeloid leukemia? And basically the answer is yes. That odds ratio is above one. The confidence interval is well above one. So yes, CHEK2 problematic DNA changes statistically give you a risk of blood cancers and specifically myeloid leukemias.

 

Now this was way back in the day when we were trying to decide if inherited CHEK2 changes were problematic in the blood system. We thought well scientifically the way to test that is to make a mouse. You make a mouse look like the people. So we give the CHEK2 change to the mouse and the equivalent position to the I157T in the mouse is position 161 for the mouse CHEK2. So the mouse is just like the people, it has one good copy and one bad copy or you can actually breed it to have two bad copies of the gene. And some people, some humans actually have two bad copies of the CHEK2, both their parents had a problem in CHEK2 and they inherited it. That's much more rare. But in the mouse they can either have one or two bad copies. We put the mouse on the shelf and let the mouse live the little mouse life. And guess what? After a very long time in mouse life, this would be equivalent to like 65 or 70 years of a human. So almost at two years of age they develop every type of blood cancer you can imagine. T cell, which is on the left, B-cell on the right, myeloid leukemia, they never have gotten breast cancer, they've never gotten thyroid cancer, any other of the solid tumors. So from a science standpoint, this would say at least that one I157T or the I200T, it's a strong risk factor in the blood system. 'cause you give the mouse that change in all of its organs and it develops blood cancer and we've just shown you the data from the human. I think now that this paper is finally accepted, people are really going to accept the CHEK2 as a risk factor for blood cancers.

 

Just coming back to this pathway again, CHEK2 talks to the BRCA1 and BRCA2 which I think a lot of you will have heard of already. We've done the same kind of question for the BRCA1 and 2 because the BRCA1 and 2 people, as you probably know, they get the breast, ovarian cancer, lots of other solid tumors, but unfortunately a lot of our patients get blood cancers as well. And so we've looked at our population played the same odds ratio kind of calculations. This is just showing you that the blood cancer can be a first cancer before a breast ovarian cancer half the time, sometimes even more than half the time. And there's a strong signal for the BRCA two in the lymphoid malignancies. And I think this is really under the radar. We even had an editorial when we published this paper that pushed back from the solid tumor BRCA one and two community saying we're not so sure we want to add the blood cancers to the list. So this is a little bit more controversial. I'm definitely on the side of thinking that the inherited BRCA one and two directly give us a risk to the blood cancers.

 

This is that odds ratio calculation again, assuming that we are a pure Ashkenazi Jewish community in Chicago, are we just seeing these cases because of the ancestry of our patients? And the answer's no. Here you can see the odds ratio well above one here, 8.6 for BRCA one 4.6 for BRCA two very statistically significant. So again this argues that we are seeing an enrichment of these DNA changes in our patients, which suggests that they are directly causing the blood cancers. We had done the mouse experiment a long time ago. We had knocked out the BRCA one, so taken the BRCA one away from the mouse bone marrow. And those mice get all kinds of blood cancers. They're very chromosomally abnormal again, as you would expect from a pathway that looks at DNA double strand breaks. And our work along with others sort of got BRCA one named as a Fanconi Anemia gene. So we know this is very important in the blood system and hopefully all of this data over time will change how the field thinks.

 

Now I do want to spend some time talking about DDX41 because DDX41 is, it is unusual in that, when we think of inherited DNA changes, we think of young people getting cancer. Actually for DDX41 people get cancer in the older age range. And here's just a figure at the top is showing you all of the inherited changes for DDX41. You see there's this pile up of this one at the first position here at the 140 position and the 500 position. These are very ancestry dependent. So if you have the A500, you probably are from Japan or Korea The D140 or the number one position, you're probably more from Northern Europe. And in the bottom we show you what happens to the other, what used to be the normal copy of DDX41 in the myeloid leukemia, you actually knock out the other copy by a point mutation. Typically this R525H. We follow one of the world's largest collections of families with DDX41. We follow about 50 families and that allows us to see things that other people haven't been able to see.

 

So I told you that people develop myeloid leukemias in the older age range like 60, 70, 80, but even as young as 17, if we do a bone marrow biopsy, those cells are not normal. So the cells look funny. They have this thing called dysplasia. We think this is very important. It's very important to have baseline bone marrow biopsies for people so that malignancies of the bone marrow are not over called by pathologists. And this is just the kind of the diagram that shows you this age phenomenon, which is very bizarre for an inherited cancer risk. Usually you think of young people getting cancer, but here you can see that cancer happens in people over 50. And in this case it's not just blood cancers. You see solid tumors in black or blood cancers and solid tumors in teal. So a good quarter of the cancers, a good quarter of the cancers are happening in people over the age of 50 and involving solid tumors.

 

So this is just a cartoon showing what we think happens in the bone marrow cancer, especially the myeloid malignancy. We inherit a DDX41 change and then we knock out the other copy with that R525H. So we think the DDX41 is directly causing that blood cancer. That's really important when it comes to transplant because what we found was that people going to transplant with the inherited DDX41 were more likely to have severe graft-versus-host disease and actually die of graft versus hosts disease after transplant. But not if they got this particular regimen to prevent the graft versus hosts disease called post-transplant cyclophosphamide. Some transplant centers are using that routinely and that seems to protect the DDX41 people from getting the graft versus host disease. So anybody going to transplant now, we insist that they're tested for the inherited DDX41 because if they have the inherited DDX41, we absolutely want to make sure that they get this therapy, this post-transplant cyclophosphamide.

 

Now coming back to these solid tumors, what we noticed were families like this on the right, another family tree. But here you see, not just the DDX41, you also see the BRCA2. So this family has two different inherited cancer risks. And what we think is really important about that is, at the top, are the DDX41 pedigrees that have solid tumors. And when you have solid tumors in your pedigree, 30% of the time you have a second cancer causing risk factor. So it's DDX41 with ATM or DDX41 with BRCA1 or with BRCA2 or with CHEK2. So we think the DDX41 modifies actually accelerates, augments the risk from that other cancer allele. So this really argues that when people have cancer risk testing, it can't be very, very narrow. It can't only be 10 breast cancer genes. It has to be very broad to understand the totality of cancer risk for people. And that's what we try to do.

 

This is just showing you that interestingly, in these families that have both breast and solid tumor, oh sorry, blood cancers and solid tumors in this case, usually the solid tumor comes first and then people get treated for the solid tumor and then they develop a blood cancer later. So that has implications for how we treat solid tumors to try to not give too much therapy and not damage the bone marrow too much.

 

This is just showing that we do not see the acquired DDX41 mutation in those solid tumors. So what we think is that the solid tumor is being driven directly by that other cancer risk. So the BRCA1 is directly causing the breast cancer. And we think that DDX41 could be influencing the growth of that solid tumor either from inflammation or from an immune system that is failing to recognize the tumor.

 

Now the last point again I want to come back to is this idea of the age. That it doesn't matter the age at which you, well, the age at which you present doesn't mean that you're more or less likely to have inherited risk. It can actually predict the gene, but we see inherited risk across the entire age range of life. So for example, for myelodysplastic syndrome that myeloid pre-leukemia, if you present as a child, you're likely to have an inherited change in the genes called SAMD9 or D9L. If you present as a teenager, especially if there's a change in chromosome seven, you're likely to have a change in GATA2. Over the adult years, from 18 out to 70, it's all about DNA repairs. We talked about telomeres, the ends of the chromosomes. And then in the elderly age group, which is kind of a shock for the field, I would say that an 80-year-old could have an inherited cancer risk. We see that DDX41. And let me just say one other thing about the age. The reason I put the MDS in parentheses here is that I think this is probably going to be true for all different blood cancers. I'll give you an example for multiple myeloma we see out in the regular age range of 65, 70-year-old getting multiple myeloma. This is BRCA2, CHEK2 and ATM. But if you're really young, getting multiple myeloma, it's a different gene, the LSD1 gene. So again, depending on how old you are when you present with your disease, it's really getting at the underlying pathway.

 

So just to come back to this idea that if we understood all the different levels, we could really develop a good treatment strategy. I've spent a lot of time talking to you about the inherited risk. Just want to spend a few more minutes talking about the layered risk as you go through life and acquire DNA changes. We now call this clonal hematopoiesis, the idea that as you're walking around your life, you're actually developing DNA changes in your stem cells, in your blood stem cells. And as those layer on top of each other, you get more and more risk to the pre-leukemia and the overt myeloid leukemia.

 

And just to talk about again, how we profile these blood cancers. We look at the chromosomes and we look at the tumor based mutational profiles. And these are what these chromosomes look like. So on the left, these are normal chromosomes. We know this is a woman because they have two X chromosomes. And here on the right, this is what it looks like when there's been a chromosomal rearrangement. And that gives someone acute promyelocytic leukemia. There's an exchange of genetic information from chromosome 15 to 17. Those have switched. And so people who are good at looking at these chromosomal spreads, they would spot this right away. This is diagnostic for that kind of leukemia. You can see from this slide there are tons and tons and tons of chromosomal changes that have been described for all of the different types of blood cancers. And we use special fluorescent tags to make finding these easier.

 

So some of you might know for the chronic myeloid leukemia, we can find this BCR-ABL or we call it the Philadelphia chromosome very easily using these special dyes. And now as I said, we classify leukemias based not only on the chromosomes but also on DNA mutational changes. This is what this kind of looks like, again, over the age spectrum and all these different genes that we look at. And again, depending on what age you present, you're more or less likely to have one of these different types of leukemias. This is super complicated. And I know next week you're going to have a talk on FLT3. And so I'm not going to talk too much about FLT3. That's right over here on the left. But all of these different DNA changes are biomarkers, if you will, for the leukemia, the acute, my acute myeloid leukemia, as are those chromosomal changes that I shared with you. And they work in all kinds of different pathways in the cell. The FLT3 is over here that sits on the external side of the cell. But you can see there's tons of signaling and tons of science that we understand about the leukemias. So we really understand what these DNA changes do. And there are lots of medicines now that are very targeted. There's too much to explain in just a half an hour. And I know next week you're going to have a specific talk on the FLT3. We classify these different leukemias into more favorable risk and more adverse risk, both based on the chromosomal changes and those molecular changes. And this is the FLT3. I am not going to go into it because I know you're going to have a whole talk on FLT3 next week. We have lots of different targeted therapies now. It's a very exciting time in the blood cancer therapy because so much science is known about these genes and their protein products. And so many scientists have developed really exciting treatments. And so we're really able to tailor therapy for our patients very well.

 

Now some of you know about acute lymphoblastic leukemia or the ALL, we do exactly the same thing for ALL. We look at the chromosomes and some of you asked about Ph+, that's that BCR-ABL or Ph-like ALL. So that is again, analyzing the chromosomal changes and the molecular changes that are driving the underlying disease. So all the themes that I talked about we have for the ALL as well. Here again are the categories, the different mutations we look at, the different chromosomes we look at for ALL. These are more kind of cartoons. The ph-like ALL is shown here on the left. For those of you who are asking about Ph-like ALL. And again, we have lots of specific inhibitors that that intersect these different cellular growth pathways that allow us to give very targeted therapy. What's the future going to be? The future is going to be that we sequence absolutely every single base pair, not only in your inherited DNA, but also in your tumor. And this is very exciting. The future already exists at Washington University in St. Louis, our neighbor, they already do this as a standard of care for their patients and they're able to identify even more chromosomal rearrangements and even more mutations than we can do with standard testing.

 

So this is really going to be the future for everyone. And these are the conventional stratifications or classifications. They do even better now that they have more precise testing. And I think soon that's going to come to everybody. So just to finish on the vision for the future, I think the future for all cancer patients is going to be to really understand everybody's inherited DNA, all of the acquired changes that they have, understand their microbiome, what was their environment, and really tailor therapy to be able to treat people the most precise that we can. I probably went a little bit over there, so I'm going to stop sharing. I hope that wasn't too science-y but made sense to a lot of you and I'm happy to take your questions.

 

- Okay, thank you so much. Can you hear me okay? I switched audio. Okay, great. That was super informative. A lot of information and a lot of very specific information. So, and I really loved how you shared the research that you're doing, which you know, I think hopefully demonstrates to the participants on this and also people who view it later, how much is really happening right now to understand these diseases and to, you know, try get better treatments to people that are targeted specifically on the root causes of their leukemia or their MDS or whatever. So I'm just going to pick a couple of questions out of the list here. Under the topic heading of CLL and SLL, we had a couple of questions there. One person asked what genetic tests are best for CLL? So you mentioned, I think you had a slide where you talked about fish testing for CML, for the BCR-ABL gene. Can you talk just generally a little bit about the tests that are done regularly? We have some information on our website, but I think it's good for people to hear why these tests are being done and what it tells them.

 

- Yeah, and that gets into a little bit of practicality. So I showed you the chromosome spreads, we call that G banding where we actually look at the chromosomes and line them up. That requires that the cells are dividing and CLL cells don't divide very often. So it's very difficult to do those g banded chromosomes on CLL cells. Also for myeloma, the multiple myeloma cells, they don't divide very much. So it's not very easy to do that chromosomal banding test. But that fluorescent, that fish test that Lindsey mentioned, the fluorescent test where I showed you the picture of the yellow signal, that's very easy to do and it does not require dividing cells. So typically CLL and multiple myeloma are done with fish panels and we use the fish probes that look for the common chromosomal changes that are seen. Some of those chromosomal changes are good prognosis, some are more aggressive prognosis just like we do for the acute chronic leukemias. And now we have a lot of molecular testing, the DNA sequencing to look at different DNA changes in particular genes. And so for CLL and multiple myeloma, there again are more good prognosis and more poor prognosis. But those are very standard tests that are done. Really these tests are done for all of the different blood cancers. It's just which genes you look at or which chromosome abnormalities you look at are very dependent on what's the underlying diagnosis.

 

- Great. We have a question that was submitted online. What additional screening is suggested for BRCA2 plus patients, positive patients besides the annual CBC differential? Should they be having annual gammopathy labs? Any role for marrow with NGS before a diagnosis is even made?

 

- Yes, it's a, that's a very insightful question. So the BRCA one and two as I tried to indicate is controversial. It's not controversial for me. I full on believe it and I've given you the data of why I believe it. But I would say the BRCA one and two solid tumor side of the field, they are not accepting the blood cancers right now so easily. So we have to give them more data. For my patients I definitely talk to them about doing a baseline bone marrow biopsy and, not to scare anybody, but we did that a few months ago for someone who had inherited BRCA two was getting all breast cancer screening and ovarian cancer screening and everything that would be recommended. But I said, well you know, I'm pretty convinced that the BRCA one and two are direct causes of blood cancers as well. I recommend a bone marrow biopsy. We did a bone marrow biopsy for that person. That person had smoldering multiple myeloma, had 10% plasma cells. So I'm pretty convinced that it's real. Our lymphoma group sees a lot of people with BRCA two and the data are coming out- actually two publications now in multiple myeloma pointing the finger at BRCA one and two as well. So I think as more data come out as more people just take away their biases and look at the data, I think there'll be more and more acceptance. So if you come to our clinic, we definitely recommend baseline bone marrow biopsies for people. That's an invasive, somewhat uncomfortable test. So not everyone is willing to have it. Some people would rather just have their blood looked at as the question indicated and we can do molecular testing, we can do molecular sequencing on the blood if people really don't want to have a bone marrow biopsy. But the bone marrow biopsy is definitely the best assessment of “the factory.” So I always recommend that if people are willing to have it and if they aren't, we can look at the blood as a mirror of what's going on in the bone marrow if that's what people are comfortable with.

 

- Great, thank you. So generally speaking, I think that it's interesting, it sounds like there are differences depending on the setting of, you know, whether it's an academic medical center like Northwestern. You mentioned Wash U in St. Louis has it sounds like NGS testing. What about for people who aren't going to an academic medical center, what's your recommendation for them and what kind of conversation should they be having with their doctor or care team?

 

• Yeah, that's a great question, Lindsey. You know, first I would say that people have, what I've presented today is some of it is absolute clinical medicine that no one would argue with and some is, you know, is emerging, that's how I call it emerging data. And you know, going to a doctor is kind of like going to a chef, you know, depending on who you go to, you know, you get a slightly different flavor of what's being recommended. Sometimes people go for second opinions, you know, to try to feel like, okay, this other expert agrees with the first expert. And I always recommend that people do that because if you've got a consistent opinion across multiple experts, then you feel very confident in that recommendation. You do have to be careful, I would say, not to doctor shop too much because then you're just collecting opinions and you're not moving forward with your care. So I would say the appreciation of the inherited risk is very well-established now but, because it wasn't taught back in medical school, some doctors are more or less comfortable with the knowledge. People have to understand medicine is not practiced the same everywhere. And so, you know, the way I describe it is, you know, like going to a different restaurant, you can order the same thing, but dish looks slightly different each place you go. Right? And so although there are kind of standard ways of treating certain cancers, you get nuance when you go to different centers. So what you'll get coming to Northwestern is not exactly what you'll get going to Wash U, which is not exactly what you'll get from a community facility. And I would say doing a little bit of getting a second opinion, making sure that different experts agree on the basic plan of care is very helpful, but don't do too much of it. You need to get your care and move on.

 

• And then I think sometimes where you go, it becomes a very practical issue. Like, you know, Northwestern has many, many different satellite sites and the doctors in the mothership, we work very closely with the doctors in the satellite sites and it might be just really more convenient for you to get care at the satellite site and you're going to get just as good care as if you come down to the mothership. In other cases there might be super rare types of tumors where it's really important to go to the mothership because that's where the expertise is. One of my neighbors a few years ago had a very, very rare kind of cancer and I recommended that that individual go to New York because the expertise was actually not even here in Chicago. So sometimes you really actually even have to, you know, go to a different city if you can afford it and you know, if that's really important to your care. Hopefully most of the time here in Chicago we have excellent medical care and we can cover things. But if something is super rare, sometimes it is really helpful to go really find the expert for whatever you have. So I think people are very smart and they have a sense of, you know, say for the families that I work on where there are lots of cancers in the family and the family feels like this cancer's a genetic disease and they've been told by a doctor, oh, leukemia's not genetic, and they look at their family tree and they're like, what are you talking about? Of course I can tell you, you know, trust your gut. You know, if you know there's a ton of leukemia or blood cancer in your family and you have the feeling this might be genetic, follow that because you're right. You know, and so really trust yourself, use your common sense and I would say seek out second opinions when you think they will validate how you're feeling.

 

- Great. That was super helpful. And, and I'm sorry that we didn't get to all the questions. You mentioned that there's going to be a follow-on next week, which I'm going to share information about right now. And that will be a webinar that is very focused on treating FLT3 AML patients. So there are several different therapies that are either approved or in trials right now for FLT3 patients. And so I think that it's great that we have the opportunity to follow on with this webinar for people who are, you know, impacted. But I it sounds like the general consensus here is the most important thing is ask the questions, right?

 

- Yeah. And trust yourself.

 

- Okay. So I'm going to share that information and this is also going to be coming out in the email that I mentioned that we'll send after the webinar, that I'll have the link in that email to register for this particular event that's happening next week. And then I'd just like to thank Dr. Godley very much for all your hard work and putting together this presentation. And you know, I think it's hopefully just the beginning of a conversation. So do you want to close with anything, Dr. Godley?

 

- Yeah, just thank everyone for their questions and then if you want to send questions to me or to Lindsey, I'm sure you know, we can put together a list of questions and I can answer them. Very happy to have everyone's attention and participation. Thanks for having me.

 

- Thank you! Savina, any final remarks?

 

- Thank you so much to Leukemia Research Foundation and thank you Dr. Godley for presenting today.

 

- Sure. Okay, great. Thank you so much everyone, and please do look out for that follow up email in your inbox and hopefully we'll see you on some future webinars.

 

- Bye everybody.