Dr. Ash Tewari presents a compilation of several of his publications in this talk. He shares his insights on the role of genomics in prostate cancer and how genetics influences the aggressiveness of prostate cancer. For appointments or referrals, please call Dr. Tewari directly at 212-241-9955. Yeah, thank you very much for asking me to give a talk talk on genomics and genetics and prostate cancer. Why a urologist or a prostate cancer doctor should know about genomics. I'll give you my background. I'll give you my understanding. But very early on I got to comprehend that not everything in prostate cancer I can treat just by denying. And in my case with the robot with that understanding, I started investigating more in depth about what is happening in the genomic level. And I will give you summary of the journey which I have taken, what we need to understand that I am in front of you and I am sum total of about 30 plus trillion cells. My body is made up of at least 30 trillion cells and many of these cells every minute are dying. Not only they are dying, they are being recycled that so this process of my cells staying in an constant lively stage, some of them dying and some of them are coming back. This entire process is a very complicated process. And what you're seeing on the screen on the right side is a cell which is a very complicated structure in itself. And as it evolves into from one cell To this 30 plus trillion cells. It differentiates into different kinds of body organs. Some of the cells become the blood cells some of the cells become the isosceles some good needs, some skin, some liver and some prostate these cells, They started from an original one, Sperm and one over and evolved into trillion cell factory in which there is a social system which exists in which one cell chooses to float around in the body carrying oxygen. The other cell work so and excreting waste products from the kidney. And there's another cell which is a metabolic factory in the body and makes deliver and then there is a skin, Their body's defense mechanisms, there is a nervous system, there are bones, there are accessory organs, all that has evolved due to a very controlled differentiation process which our body, our species has learned over millions of years. But this process is not perfect meaning whenever there's this new cycling of the cells which is going on, they generate back into its normal form. But sometimes there are mistakes which happened and those mistakes can actually result in cancer. And that's the reason. As a surgeon, as a scientist, I have to learn about what is happening at the basic molecular level which can impact the whole bodily function. On the other side of the screen is showing something what we call cell cycle process. Most of the cells they are staying dormant, meaning they are doing their job but they have no desire to multiply. But there are certain cells in the skin and certain cells in the lining of our gut, the certain cells in the bone marrow, they have to multiply again back because they are having a issue with the sell debt and the cell regeneration needs to happen and this entire process of a resting stage versus what we call a G one and G two stages days are the cell cycles, which is very delicately controlled. Not every cell can go onto a synthetic phase or go onto a G. One to the G two phase or go on to the main topic phase. There are certain checkpoints which exists and these checkpoints are at three different levels and these are some kinds of proteins which actually control the entire process. It checks on whether there isn't enough organelles present before the cell is ready to divide, there is enough DNA made and duplicated before the cell is ready to divide. Has the DNA duplication? Has that process been taken through the quality checks or not? Because we don't want to create a cell which is not the perfect form. That entire building check and balance mechanism is what we call our life and understanding about that life is the journey I'm taking you through through the cancer genetics discussion. If I have to sum up, why are we having this discussion as a surgeon. As a scientist. It can give us an insight as to why prostate cancer habits. Genomics will help us in understanding who is at risk, how we can better diagnose prostate cancer. We have a diagnosis of prostate cancer and we can use genomic tools to make a better prediction as to which amongst these 1020 patients is likely to be a very advanced growing cancer versus one, which will be very indolent genomics can tell us, we can manage the recurrence better just because we know what kind of a cancer has come back and today we are able to develop certain treatments which are targeted towards a particular genomics of time. And as the end of this discussion, you will see, we can even devise body's own defense mechanism to fight against prostate cancer. If we understand the genetic details of that specific cancer, what we call personalized genomic vaccines can be made. So genomics is not just an intellectual exercise, it's going to help us be a better doctor, better surgeon and a better clinician. Let's go through this journey. I'm showing you on the left side what I get to see as a surgeon, as a surgeon, I see a structure. I see an organ. I see official play inside the tissue. I can understand where one structure ends and the other structure starts on the right side. What you're seeing is a gross specimen which has come out and that is the gross pathology, which is telling me that I have taken the organ out and part of that organ is a diseased, what we call cancerous in this case, on the lower left side, what you're seeing. It is assumed in mechanism. First I saw the structure. Now I'm seeing a gross image and now I'm getting deep inside under the microscope, my magnification. I can see structures that where the cancer is, how Canada's trying to escape. And if cancer has become from an incurable, incurable to an incurable cancer because it has broken through the anatomical boundaries on the right side. What I'm trying to suggest that all that is happening in an organ in a tissue, in an microscopy. Actually, he's driven deep down inside the cells by certain proteins minded, those proteins are making a cell become from a normal to a rogue cell. And that understanding of those proteins, those pathways those molecular pathways is where the genomics comes in. So with this background, I want to show you a first ever case of in prostate cancer which was diagnosed in About 2700 years ago. And that happened to be a king of an area which was between the Russia and Afghanistan. And that was known as the King of Israel. That king was a very strong person but was the first case of documented prostate cancer in which we have been able to confirm that because of no other method. But for the genomics that allowed us to confirm that he had a prostate cancer. What you are seeing in the bottom is the journey which happened in that patient from a single cell to a clump of cells. We have more invasive pathway and the answer became totally out of control and on the right upper side what you're seeing are the bones which became brittle, eaten away by the cancer and that finally killed that king strong person. Prostate cancer started in a cell, started in an organ grew beyond organ and over to the whole body. That all can happen. And I want you to take through this journey of going inside the human body. What you're seeing now is in the bladder, then you are seeing a prostate and in the prostate, what you are seeing is one rogue cell decides to become too. two becomes 4, four becomes 16 in tentacle to become millions and sometimes billions cells up to this point, it's all okay. But then it gets to a point where it reaches the blood vessel, reaches a nerve and gets out of the boundaries of the organ where it actually took the origin from Now, it is becoming a problematic answer. It is becoming what we call an invasive cancer. And then it will become a regional cancer. And then finally, it will become a Matar City cancer which will go to any part of the body. It went to the bones just like it went in that King of the Azra, how that single cell evolved from a very normal prostate cell into a rogue cancer cell became so angry that it took over, go through all the control mechanisms and then went on to overrule the whole body and in that process killing the human that all was happening because of certain changes which were happening inside the cells. And as a scientist, we can understand those changes and that is what we call the genomic details of the cancer biology which can have an impact on the final outcome. Because there are certain treatments which may be there if we understand what exactly is happening inside the gene which is abnormal and can be fixed that cities and we need to understand the economics and I want to bring you back into the discussions about the proteins. Everything which happens. You are watching this video and this video is being watched by your eyes And there is a protein in the retina known as reduction and that is changing the chemical structure and creating light into a neural impulse. It's going inside through your nerves inside your brain and the neurotransmitters are acting on it. The very fact that I can speak, I can move my hand. It's because of certain muscle proteins are acting and allowing my voice to come out my fingers to move around and I can change my gesture to look at it all that is happening because of proteins inside the cells. Those 30 plus trillion cells I talked about. They have proteins inside and the proteins are very, very important part of her body because not only that they can allow us to see or hear, but they make the structure of the cell. They act as a messenger of the cell. They are involved as an enzymes. They are involved in the cell communications. One cell talking to the other cell, hey, oxygen has arrived or an invader. Is there all that messaging system is happening through the enzymes or to the growth factors or through the signals. They're all made up of different forms of proteins. Those proteins can also be very helpful for us to build up an immune mechanism so that it can find and fight and invading bacteria or invading covid, covid virus, all that is being managed and artist stated by proteins. So proteins are our acting capitals. Guess how these proteins are made. That is where the gene discussion comes in because proteins are not only involved in the day to day functioning as I said, there are certain checkpoint inhibitors the process of entire cellular division itself is controlled by the proteins either as a structure or as a messenger. And this entire process is controlled precluded by the genes. And that's what we need to understand. That each one of us have two books of goods given to us, one by my father And one by my mother. These two books have the entire genetic code written to us so that we can read it and we can copy it and then we can create a specific protein whenever and wherever it is needed. Each one of these books has 23 chapters, 23 chromosomes. These 23 chromosomes are coming from father's side and from the mother's side. But these chapters have got small paragraphs. These paragraphs focus on one particular recipe. Let's look at the recipe is we want to fight a virus. We have a different kind of chemicals we need to produce. We have a little lack of oxygen because we have gone to a higher altitude and we need to get in more R. B. C. S in our body. Different other kind of M protein needs to be produced. This all recipe in a very perfect form is written in an over genetic Mhm. This is our judo and the alphabet in which these paragraphs and chapters are written is known as the language of nature, language of life or what we call A D. N. A. Each one of these chromosomes is a very complex lee folded form of and DNA that is wrapped around and I'll come onto as to how this wrapping even can have an impact on how things are functioning. But this D. L. A. Has segments these segments and what we call genes. A particular paragraph of a particular chapter talks about a specific functioning and these are what we call genes. And guess how many genes we have. We may have more than 20,000 genes. But at least these 20,000 we know And these 20,000 genes are coded or written by the DNA, which we have. And the intermediary of this DNA is DNA is the book. We have a scanner or a reader which is an irony, irony, three different kinds they stay, get the job done inside the nucleus, get the RNA out and go and produce protein. Our favorite protein. And that entire process is very complicated then because D. N. A message through RNA is making a protein but there are only 20 different kinds of amino acids and these amount of assets can be recycled. Repurposed, re folded, recombined And then shapes change to 20,000 of the proteins. All that is happening inside those small cells of ours. And this entire process is a controlled process. So that's the reason we wanted to understand how this process is being controlled. Book exist. But we don't take care of the book. The DNA messaging gets a little bit distorted. Message was there but the reading didn't happen very well. So what we call a mutation happened. A particular segment of a gene was either a misread or over amplified or chromosome because of some reason got shattered. And then God recombined and the net result was there was in distortion in the actual true meaning of that gene. And that's exactly what we call mutations mutations heaven every time mutations they happen in everybody all the time. But many of those mutations are not meaningful. Some of the mutations are meaningful what we call the driver mutation and some of the mutations are not compatible with the life. So what's happening while mutations are happening there are different kinds of mutations can happen. You read it wrong but when you typed it to type the drugs, it's like in jumbled up typewriter in which the two alphabets are righting a wrong message. So this is a single alphabet is being transcribed wrong. But if a small segment is the problem, that entire thing will produce the protein. But instead of producing a squash it will latch squash, sugar to salt. And guess what? That drink is not going to be very useful because it was supposed to be sweet. But somewhere the letters got mixed up. And if that happens in a very relevant gene which is producing a protein which is critical with the life of that cell, we cannot let that sell go on. And that is where the control mechanisms they come, body has a very good control mechanism. Not only it's doing a proof reading more than once, it is also looking at the final product. And if the final product has a problem, it has to make a decision. Is this still fixable? We have a mechanism known as the DNA repair pathways or is this cell not compatible? It's so defective that if we continue it leaving living it will create problems. Then that cell has to die and be steer that sell towards what we call apoptosis. That cell decides, you know what I live my life, I have a defect and if I don't commit suicide, I will be damaging my neighbors. So this is a social system built in an hour, millions of years of evolution and this entire process is very well controlled. So what we learned proteins were important genes are in the chromosomes through the DNA mutations can happen. But body has a very decent safeguard mechanism of dealing with these mutations. So I started getting more and more involved in this gene and the how things are happening. So genes are the ones which are controlling the proteins and one cell to the trillions of cells. There is an total art in how this entire DNA is packaged by the way. I mean let's say more of a trivia question. And basically each one of us have enough DNA folded very meticulously inside of ourselves. That if we unfold it, we can go from here to son 300 times enough length of DNA exists in each one of us. That if we unfolded that distance will be from here to sun, not just one time 300 times. So basically there is a lot of information is kind of arranged and coded within our DNA. And every now and then DNA having a special protein around it. What we call his stones, these his stones, they allow you to kind of do the packaging in a way so that it is compressed within a very small segment and sometimes the proteins around the DNA also make sure that not everything which is out there in the DNA is coded. So this is a very precise machinery. And we, as a surgeon scientist and now you all have to comprehend it. So I'm trying to simplify it as much as I can so that you get the bigger picture. Obviously there are textbooks and books for us to get into the deeper dive into this. So D. N. A. Is an important part nuclear soames. His stones are very important part of this entire factory. There is a lot of DNA in our body and there is a lot of methods in which this entire thing is controlled. I also want you to know without getting into too much of the detail. It's like very early on in our career. We were taught how to read the EKGs and we were given the status scopes to hear the heart murmurs and the sounds and all the signs and symptoms of the entire general exam. Same way a new field has come up and there are different ways of looking at the gene. There is in phenomenon known as a whole genome sequencing. There is an exam sequencing. There are even what you call the methylation for the histone sequencing and there are ways to get into the single cell and what we call a single cell sequencing. So we know that the D. N. A. Has jeans genes control proteins. Protein is important for this timely and regulated duplication of the cell which is the reality of life. Everybody has cells which are dying and some cells need to cover in that process. Certain cells misbehaved and when they misbehave they become cancerous. And my next transition point is, what do we mean when things become cancerous? And I want to simplify. There is a very important paper which has been written about the cancer and cancer cells share certain basic tenets why they become cancerous and these are known as hallmarks of cancer. There is a very complicated diagram on the left side in which we talk about that there is an phenomena of overcoming the growth suppressors. There is a problem with the immune evasion but I will simplify this entire process into imagine you are having a car ride, you were driving and at a curve you're supposed to take your foot off the pedal so that the accelerators closed down. Suddenly you realize that actually the car's accelerator is stuck. If that happens, car will not slow down and we'll keep going. Same thing is happening in in cancer cells Somehow cancer cells was supposed to slow down in a division process because there were enough number of cells and certain accelerators are stuck and we call them oncogenes. Anka genes are certain proteins, certain genes, certain molecular pathways within the cell would just keep telling the cell divide divide divide divide divide, that should have slowed down, but something has happened to that cell that it is not slowing down, okay, you cannot take the accelerator off. But you can in that situation apply a brake and you apply a break. And then suddenly you realize that the brakes are also not working what I mean? Not in a normal cell when there is a hyper accelerated pathway which is active. There are certain breaks which are built in and these brakes are known as cuba suppressors. Um are suppressors can block the entire pathway and then say hey you know what you need to slow down but cancer cells somehow figure out how to even override that control and what is happening that they cells they don't stop. So on one side there is an oncogene which is driving the mutations driving the cell growth and the other side. The normal control mechanism is also not working what we call the tumor suppressors are not working. I'll give an example of an oncogene. Is a rash. Is an oncogene. P three chinese pathway is another one which is involved. The P. 10 AP. are what we call a regular hummus suppressors. Then comes the third thing that, okay, sooner or later if you keep dividing the normal cells have a limit known as Limit of about 60 to 65 cell division, after which cell runs out of its dividing ability. And then that is controlled by something known as telomeres telomeres at the end of the chromosome. And if you don't take care of it. It phrase and the DNA itself cannot divide And it's known as the hip flex limit. Not limit is there because of shortening of the telomeres. And we hope that the cancer cell after X. Amount of divisions will run out of the telomere and it will stop dividing. No john cecil has figured out how to rebuild the telomeres. So the telomerase enzyme is there and that enzymes keep regenerating back that portion. So multiple things are going on. And then you hope that it will run out of the gas. The carburetors are problematic and it will run out of the gas. So What we call the normal energetic seven cell is that the Mitochondria works under aerobic conditions and the aerobic conditions produces 13 and still needs those atp's in a very efficient manner. Cancer cells have hacked the carburetor and they can work in a non Arabic pathways and they produce more lactate in all those things. And that lactate is used for some other kind of infrastructural phenomena and they have rigged the whole carburetor system. So this entire process is happening inside the cancer cell and we need to understand what's happening and what is driving at the genetic level, then think about you're driving this car and it is just going fast and fast and fast through the road, not respecting any kind of in control mechanism. You hope sooner or later the traffic police will get to you and will finally force you or somehow managed to stop it. Yeah, that's supposed to happen to the normal cell. But the cancer cells have figured out how to not be seen by the traffic cops. So our immune cells are supposed to stop it. But the tumor cells have figured out how to hide their antigens so that they are not exposed and they can go on for a long time, guess what this all is happening in in cancer cell, which is just refused to follow the social rules of not dividing beyond a certain number. Next thing comes that the normal cells will run out of gas, meaning they need oxygen and after a while, when the number of cells grown beyond a certain limit, it will be needing more oxygen, but there is no more oxygen to come. But that's where the cancer cells become a little tricky in denial, they will produce what they call angiogenic factors. So they will create chemicals which will create sprouting of the capillaries so that they get a preferential blood supply of more oxygen coming to them. And that phenomenon is known as angiogenesis, that all is happening because of certain enzymes, certain proteins, certain genes are acting and helping cancer cell in getting all this achieved few other things are going on. one of them is that the gene itself in that cancer cell is not very stable and we call it genomic instability happening. The other thing is when Dave's so much of an unregulated cancer growth is happening. The body produces some inflammation and inflammation now concludes with the cancer and making it even more aggressive. So pro cancerous inflammatory processes one of the hallmarks of the cancer. But to me, one of the biggest tools which cancer cells they use to become from in one solitary cell to a billion cell bass is what we call this vehicle, which was only trained to drive on a highway on a road changes from in regular cell to what we call an all terrain vehicle. What is happening? The cell, which started early on in de differentiated cell has become differentiated to be a prosthetic cell which is supposed to be not moved around, is supposed to sit on in basement membrane, reduce certain chemicals and the PSAs and all those things. This cell is regressing backwards to a point that this regression will result in what we call an epithelial to mesenchymal transformation. This car is now becoming an all terrain vehicle. It can grow within the collagen network outside into the human micro environment. It can drill holes using the inflammatory cells and other methods and metallic preference to go outside the capsule. It will collude with the nerves to find its way out. It will then go to the lymph node, it will go to the blood vessel and now it has become a metastatic niche is circulating everywhere and finally, sooner or later it will find a new home will produce this entire process one more time. And this is what is the journey of the cancer. And this complicated slide in front of you summarizes that, that many different proteins, many different genes, many different pathways, what are doing this entire damage to the human body. Okay, It was a little complicated, but we had to go through this because in order for me to explain, I myself went through this entire process and it all started when I started collecting tissue during my robotic surgery to understand what is happening deep inside the cell. I started taking tissue from the different parts of the prostate. I started doing as single cell genomics and I started looking at the what we call the copy number variations and even in one different location, one prostate, one cancer, different parts of the cancer were in different clones that resulted me in understanding that this is in clonal evolution which is happening. That brings me to a different thought. What I'm going to introduce that Prostate cancer, Carrie's name, prostate cancer in 10 different patients. You think they may have a different stage. They may have a different lease in grade, but at a fundamental level, at a molecule level, at the gene level, at the protein level, at a pathway level. These 10 cancers will be very, very different and I'll get to that why it is important. But cancer may become a very aggressive cancer taking a totally different pathway and that is what is what is being shown here, it's one of the first papers which I wrote with my colleagues in Cornell and at the Broad institute in Harvard system, you're all my patients, they have a different lease in grades. But when you look inside what you are seeing here is known as circle grab circle Graham is in E K G for the jeans. Each one of those numbers represent one chromosome and it is also showing whether a part of it is deleted, added, translated and if it has translated where it has gone and got attached, this is what the circle graham is. And just looking at a grossly look at the right lower one and the left upper one. There are two different kinds of circle grams and that's exactly what is happening at the genomic level. Seven different patients, seven different genomic types. So this phenomenon is known as an intern humourous estrogen initiative meaning between these different patients don't expect them to have the same kind of in cancer. And we started looking at what exactly was going on. And these are some of the papers we wrote as to what is happening at the mutation level and what was happening in the epigenetic level and how exactly this entire process was happening. What interesting thing came out, what we call it, punctuated evolution. Certain mishaps were happening early on. Then small mishaps were happening a few years later and then finally one more disruptive process happening and the whole chromosome got shattered. And once it got shattered it just got it tried to re fix it back but when it was fixing it back it was connecting here to the nose and finger to the thumb. And that kind of restructuring is known as chroma trip see and chroma plexi. And net result was a very abnormal DNA was being produced and that contributed to the genesis of and more aggressive prostate cancer. And throwing into this. The discussion about the androgens, androgens in prostate cancer can impact almost all of these pathways which have talked about the ankle jeans, the suppressors, the inflammation, the angiogenesis, genomic alterations. All that can be mediated or propagated by the androgens. And that happens to be the main treatment modality. What we are dealing with it in prostate cancer. So this just tells you how inte greatly involved this entire metabolic pathway is the only reason I can talk about it is because of understanding of a little bit more about the genes. I don't want to re go into this entire process. But I will show That growth factors of cells becoming 12 billion is happening on the left side. But what I worry about what is happening on the right lower side, how the cancer cells are becoming from an average cell which is number increase in mass to a more invasive capacity cancer. And this all can be quantified by different genetic tools which we have now. So that's the important part. And we finally, no that in a simplified version there are a few different kinds of prostate cancers. I'm not talking about the gleason grade, I'm not talking about the stage of the cancer, I'm talking about that. 71% of the cancers will have a bottom line abnormality in the hundreds and receptor molecules but 49% of the patients will have something totally unrelated, which we call the pi three chinese pathway just to connect you back. And what is this behind? Three kindness pathway is insulin receptors. Sugar insulin activates the metabolic pathway inside the cell and that is known as the P. Three canes amateur pathway. And ultimately it manages the certain parts of the metabolic system that I will call it sugar addiction. So 49% of the prostate cancers have something abnormal in the p. I. Three Chinese pathway, which is something to do with the insulin pathway. Then 13% of the patients have an abnormality of what we call it D. N. A repair pathway. Remember earlier when I was saying that the D. N. A. Is checked for the proof reading and if it has a minor abnormalities, this spelling mistakes, it can be corrected and that entire process is known as a DNA repair pathway. Those DNA repair pathways are also known as the B. R. C. A. Because that is very famous group of certain genes which are involved in the breast cancer discussion. But the similar gene group is involved in prostate cancer also. And 13% of the patients with prostate cancer who have an aggressive prostate cancer actually have a problem with their fixing mechanism of DNA repair. So DNA is being damaged in a normal form, but its repair mechanism is not working and then mismanaged damaged DNA is allowed to become a living still in the community and that sometimes happen to carry a certain particular genomic abnormalities of the one which we just talked about and becomes the cancer. Then we talked about the cell cycle discussion. Do you remember that there are three different cell cycle blocks so that the cells are proofread and allowed to go to the next level only when they are good. There may be a problem in those pathways and if that is sure 21% of the time and we are finding that there is a problem there. How does it matters? DNA repair pathway. There are certain medications which are out there. DNA repair pathway also leads to what we call a mismatch issues or cells become a little bit more a recognizable to the immune system. So nutritional pathway goes up. Sudanese repair pathway. If we recognize as an issue we have certain medications built in for them, Someone has a P3 kindness issue and we are just depriving them of 71% of the androgen receptor, they're not going to budge. We need to understand what is happening in a molecular level to a particular patient so that we can keep them both targeted treat. Even in the androgen, there are issues with the splice variants. There are so many details which we are getting that we can tell her the treatment not for an organ, not for a tissue, but for a gene, but for a chemical but for a target. And that is where this entire field is evolving. And this is just a good example of how understanding of the genes allows us to reclassify patients. Then comes the discussion about the genes and there are two words I want you to understand so far, all what I have talked about is what is known as the somatic mutation. The genes within the cancer are abnormal, rest of the body was doing fine. And those abnormal cancer genes are somatic mutations and they took over the process and they are ruling right now. But there are certain mutations which are present right from the birth. And these are known as the germline mutations, meaning they are present in almost every cell in the body retinoblastoma gene you have heard about. There are lynched syndromes in which there are certain abnormalities built in inherited bias, which predispose us for more cancer. So that is known as a germline screening versus going deep inside the cancer which is already developing And that's known as the somatic screening. It's very important for us to understand both the genomics. One is in all the cells which is a germline, another is in the somatic cells which is happening within the cancer cells. So what are the practical utilities of this entire discussion? And I will take a couple of scenarios. I'm not taking all of the scenarios many times. We do the prostate biopsy and the biopsy comes back to be negative but the patient's BSE continues to rise and we don't know how to advise them supply negative biopsy. We have a tool which is based on what we call an epigenetic or a hallow effect of the DNA methylation project, in which tissue, which is not showing cancer on a microscopic level, on a genomic level is still showing certain changes which are not yet there but a pathologist to pick up that is a cancer, but it is showing a predisposition that in the next three years, five years this patient's tissue is likely to change into what you call cancer. If that is positive, you will have a different kind of in follow up regimen into a patient and at least in the United States, that's available as in confirmed MDX. And it's a good tool for me to use whenever we are dealing with a patient with a prior negative biopsy. We found the cancer Cantidad. The gleason 6th or a gleason 73 plus four. What what to do with that cancer. There are many different kinds of treatments which are available and the patient could be a very adequate treatment for what we call a watchful waiting or an active surveillance. Some of them would like to have focal therapy. Some of them will be a very good candidate for a nerve, swearing, robotic prostatectomy and some of them needs radiation. How to kind of quantify sub stratify a patient who already has a diagnosis of cancer. And that is where different other kinds of tests which have become available. And one of them is known as the polaris which gives a sum total of these different kinds of in variables. I was talking about it. It gives a risk profile for that patient as to what's the likelihood that this patient's cancer will behave more aggressively down the road in the remotest, one of them is known as an encore type DX which has different genes which are associated with the worst outcome. And there are certain genes which are associated with the good outcome stromal response genes and the proliferation genes are associated with the worst outcome. Hundreds and signaling and cell organization genes are associated with a better outcome. So knowing what kind of in genes which are there in that listen. Same similar looking but very different insight can have an impact and we tend to use a lot more for our selection of the patients on an active surveillance. The third one is a decipher it has multiple genes and it has 22 different kinds of an RNA biomarkers which it has used, it kind of gives a risk profile as towards the likelihood of this cancer will behave more aggressively versus less aggressively. And this can also be used not just in the biopsy tissue, but we tend to use it after a radical prostatectomy. Understanding words the likelihood that this bench patients cancer trying to come back. This is all happening because of our understanding of the gene and it gives a big picture polaris on codex decipher all of that combined or individually will help us in choosing the patients better for active surveillance. It will help us in identifying which patients may actually need, what we call an adjuvant treatment, which patient can need a new adjuvant treatment. There are newer kinds of treatments which are becoming available so that the recurrence rates are lower and that all can be tailored through this approach. Even looking at the pathology There are certain pathways like I-67 and the hundreds and receptor. You can go deep dive into an image analysis of the pathology and upgrade that with what you call an immuno history chemistry and you can get to the genetic level and that and your pathology becomes an augmented pathology, it becomes in genomic guided pathology at genomics and I have been involved in this paper with my colleague Carlos Cardoen, who is the chair of pathology here, it makes an impact in whilst making a decision. Just looking at the history pathology. So I would just say this is a gleason six. We have a little bit more angle into that and then comes a new field which is evolving and I'm very happy that my group is quite involved. The M. R. I. Is becoming more and more sophisticated and looking at the MRI images. Looking at the biopsy images, we can combine all that and come up with in what you call a better understanding how it correlates with the genomics. So we did all that. We correlated the genomics by rod and History pathology and found that there are different pathways which are being involved in empire at five vs. Pirot four. And in fact there are the people who have done work and showing that certain invisible cancers have got a genomic pathways. So there may be an staying under the radar slept word of in prostate cancer which is using certain genes which is not allowing us to pick up using cover in which the imaging methods and genomics can unmask them and that all is happening right now. Then there are certain racial groups which are having more prostate cancer. And we have done an analysis as to what is going on and certain factors are emerging which are immunological which are biological which are inflammatory and we are finding certain beaten losses. We talked about the piton as in one of the suppressor genes. We talked about the epigenetic analysis that talks about the methylation which may be happening more in an african american. It helped me in making a better decision, It helped me in better understanding, it helped me in defining why a particular racial group is having more prostate cancer in which kind like is it having an impact on me treating the prostate cancer? And the answer is yes. Future is here because we have done a couple of analysis in which we are looking at the immune checkpoint therapies and the targeted therapies. We can now know the patient has an androgen receptor kind of problem or enduro at the clean kind of problem which will have no impact from an androgen deprivation rather will lead a totally different kind of treatment we know which patient has in DNA repair pathway discussion and so we can put them on the path inhibitors very early on and who amongst these will be benefiting from the chemotherapy. All that can be done based on our understanding of this entire process and also we get to know not just the cancer cells but the cells which are surrounding the cancer, what we call it. Human micro environment and tumor micro environment is very rich with certain immune cells and immune cells operate through those molecules and these molecules are controlled by the genes, the proteins molecules, genes that interaction comes here and we can be very precise in understanding how to boost up the body's own immunity to control this. And we have written these different papers and one of them which is we are very proud of is we are doing what we call a personalized genomic vaccine, cancer cell. In order for it to become cancer. It sometimes hacks certain normal control mechanisms and in that process it has some unique proteins. It brags about that, it has those unique proteins but that unique protein makes it a target because the normal cells in the body don't have that protein cancer cells because of bad behavior, has developed those proteins or is using those proteins for their benefit. But we can recognize that we can train our own bodies T cells and NK cells to go and fight only those cells who have that abnormal protein architecture. We call it new antigens. And we have a whole vaccine trial going on in which we are developing a personalized vaccine which will work for Mr smith or will work for another individual patient and it will be very unique, very targeted. And it is happening as we talk. We have written books on this entire topic. I'm about to put together a second edition of this whole prostate cancer comprehensive book and that passion about understanding the biology beyond just focusing on the nerve sparing aspect which is my full time job. I really want to thank the organizer for allowing me to share my perspective about the genetics genomics and how it can have an impact in the patient care. Thank you very much.