Dr. Jianfeng Xu Video (Text Version)
Clinical Validity and Utility of Inherited Genetic Markers in Prostate Cancer Risk Prediction
Natasha Kyprianou
It is a pleasure to introduce the next speaker, Dr. Jianfeng Xu. Dr. Xu is the Professor and the Director of the Center for Cancer Genomics and the Associate Director of the Center for Genomics and Personalized Medicine Research at the Wake Forest University School of Medicine in Winston-Salem, North Carolina. Dr. Xu has been a pioneer in the field of prostate cancer genetics and functional genomics with major contributions to molecular epidemiology and SNP analysis. He currently serves as a member of the Prostate Cancer Research Program Integration Panel in the Department of Defense and the NIH Epidemiology of Cancer and Genetic Study Sections. Today, Dr. Xu will share his impressive knowledge on the clinical validity and utility of inherited markers in prostate cancer progression; Dr. Xu.
Jianfeng Xu, M.D., Ph.D.; Professor of Epidemiology, Cancer Biology, and Urology, Director, Center for Cancer Genomics, and Associate Director, Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC
Thank you Natasha for that great introduction. So it is a great honor for our group from Wake Forest and also Bill Isaacs from Johns Hopkins and Harold Grumberg from Karolinska Institute of Sweden. The work I am presenting in the next 10 minutes will reflect our collaboration. It is also a great recognition for research funded by DOD to study the genetics ability to prostate cancer. I will talk about the DOD funding impacts our research in the genetics ability to—prostate cancer and which is really my field and talk about a genetic variance—inherited genetic variance we call SNP and one of those common most inherited variances as SNP and that predisposes to prostate cancer.
I will tell you about the breakthrough in identifying prostate cancer with such an SNP, and how we use those SNPs in risk prediction to add in for high-risk individuals and finally I will tell you how we actually validate those things in a clinical trial setting. First the DOD and my research career in prostate cancer—in 1998 I began to receive DOD funding as a subcontractor PI to build Bill Isaacs’ DOD-funded project on search for hereditary prostate cancer. In 1999 I started to receive my first ever grant, so it is building my research career from DOD, this first grant, and later on in 2003, 2005, 2006, and 2007, I continued to receive funding from DOD as a PI, co-investigator, mentor, and subcontractor PI. In 2009, I decided it is time for me to pay back so I serve as an Integration Panel Member for the DOD.
This is showing the impact of DOD funding on my research and from a research perspective in 2000—in 1999, 1998, at that time we know prostate cancer is an inherited disease but we do not have any clue about specific genetic variance that is responsible for this inherited component. In 2007, it doesn’t solve those genetic markers have been identified not just from our group, most actually from other research in this field. In 2011, now we are talking about how we use those information in the clinical setting. That is the DOD funding impact on my research. My entire career you can see at the beginning, I started working under my mentor which was Bill Isaacs, sitting there. He is actually not that old compared to me; actually he’s younger than me (looks younger than me), and there I continued to develop my own research career as a PI, and in the last couple years I served as a mentor for DOD funding, so you can see the trend.
Unfortunately there’s also a sad effect on my hair. At that time it was full hair–half gone. Now I can use “countable” for my hair. So nothing is free. I summarize my DOD experience as iDOD. So together with my iPhone, iPod, and iPad, I figured out how to impart the DOD to my research and my career. So I call it iDOD. But anyway okay.
So prostate cancer is an inheritable disease; so the question here, I’m not just talking about those rare hereditary prostate cancers. I’m talking about prostate cancer overall in general and that we find out approximately 42% of those variations that put you into a prostate cancer is due to genetics, so it’s 42%. You can see—42%—it is the highest amount, the major type of cancer. So, now the question, where are those genetic markers that are actually responsible for those hereditary genetics ability? In the last 10 some years, 20 years, we tried very hard to look at the candidate, possible ways to try to find where is this genetic variance in those genes responsible for but wasn’t very successful. Then in 2007, there is a breakthrough in the methodology; it developed in a method called Genome Wide Association. It is called the GWAS. The idea, if this is an inherent genetic disease you must inherit something from your parents. If they are not in those candidate genes, if they are not in those pathways they must be somewhere in the genome. Therefore, if you systematically look for the entire genome, you will find it. So I describe it almost like the looking for the needles in a haystack; it’s very difficult.
But if we use a Genome Wide Association approach like a magnet, it will find all those things and that is what happened. This is the whole genome, chromosome 1 going to chromosome XY, so we look from beginning to the end. Chromosome 1 all the way chromosome XY, one very, very fine resolution, and in 2007 like I say, after GWAS and a couple groups identified five genetic markers, three on chromosome AQ and two on chromosome 17Q that’s responsible—that increase risk for prostate cancer. In 2008, a lot more and by 2009, there are 33 genetic markers. So we did not know much about the risk factors for prostate cancer prior to this age, race, and family history. But in 3, 4 years, we found 33 more risk factors. And what are those genetic variances?
First of all, they are not really in a candidate gene—in a known gene; most are actually between the genes. Second of all, they’re very consistent. If you do study right, you will find those genetic markers in your study population. Lastly, although each of those variant SNP contribute very little to prostate cancer risk but as a combination they actually contribute a great impact on prostate cancer risk.
So in 2008, we started to look at the first five to see as a combination how much influence they have on prostate cancer. If you are lucky, you do not inherit any of those five, so you have zero in population. If a way to protest, we will figure out how many of those markers you inherited. If you are lucky, you don’t have any; if you’re unlucky you have one, two, three, four, or any of those five. If you compare now—inherit two of those five, your risk compared to a man without any of those things is twofold. If you inherit any of this, it’s threefold and fourfold and if you have five or more it is tenfold. This you actually see in one, two, and a combination of study population. Later on we actually expanded to 14 because we continued identifying more, so when we see the 14 actually it is very, very informative. If we are able to genotype (measure your SNP from your blood or saliva), we can tell you your risk way before you develop prostate or your risk for prostate cancer. Someone can have a risk as low as 2%, 3%, 5%; someone unfortunately will have risk about 52%. On average, there is 13% risk of prostate cancer in the United States. So you can see those 14 markers allow us to differentiate your risk from very low to very high.
Now if you have low you do something different; if you have high you of course will do something complete different. The question, what is our remaining question? So is this valid? Those are actually from previous studies from case-controlled. Can you really see from a perspective of clinical trial and how those genetic markers compare to existing markers like PSA and DRE and those kinds of things and the more important—whether the genomic marker adds value to those things. Those questions really cannot be answered in case control studies but can only be answered in the trials.
We look then for just—provide the study population to us; we look this thing in the reduced five. So it is a randomized double-blind clinical trial for reduction of prostate cancer using the dutasteride. The important thing of this study population is about 4,000–8,000 men with PSA at 2.5 to 10; it is in the reasonable area and we snipped a biopsy. They have good baseline measurement as well as those genetic DNA 433 marker and because they measure at a time when this started this study 4 years early and they will follow up in 4 years and they have a biopsy in year two and year four, so we can really systematically compare the genetic marker with existing clinical model and how useful it is important.
And here is the result. So in our two measures—how good it is—the predictor we use as you see; if it is 50% it is random. If it is 100%, it is perfect. So DRE is 51%; family history is 53%, and the total PSA is 54% and the PSA velocity is 59%. Look the next one is a genetic marker at 59%. Okay. So genetic markers based on those 33 SNPs performed as well as, if not better than, most clinical available. The more important thing; you can see the last two columns. One is the best combination of clinical models to predict your positive biopsy, and the last one is the best combination, pros-genetic marker. You can see it is getting close to 67% which you see the improvements. So the important question is genetic markers add value to the existing clinical model.
Finally, although I did not show it, you already see how genetic markers can be used to determine who should go on repeat biopsy based on those findings and the next question—additional question will be whether we’re able to identify high-risk men for target chemoprevention. Actually we do have data from the reviews trial, which is very encouraging. I do not have an opportunity to tell you today but also I think we can see whether we can add in for high-risk individual for target PSA screenings. So you already can see the impact of the DOD funding on this area of research on the clinical side of prostate cancer.
I would like to acknowledge the other investigators from Wake Forest, Hopkins, Sweden, and TGEN and also GSK for their support in this research area. Thank you for your attention.