Placeholder Image

字幕列表 影片播放

  • Integrative Analysis of Genetic and Epigenetic Alterations

  • in Lethal Metastatic Prostate Cancer

  • Vasan Yegnasubramanian, MD, PhD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University

  • Our major goal in our research is to try and understand how genetic and epigenetic processes

  • can cooperate in making a cancer cell be very aggressive or even get the cancer cell started.

  • The DNA in a cell is what tells a cell what to do and each cell in our body has the same

  • genetic code but they actually behave very differently. And so there's actually a level

  • of coding beyond the genetic sequence which is called epigenetics--beyond genetics -- that

  • actually helps those cells figure out what to do and when in order to behave the way

  • they should so that a brain cell doesn't behave like a liver cell, so on and so forth.

  • In cancer cells we know very well that they can change their genetic sequence so that

  • they become different and actually can escape the rules that normal cells live by. They

  • also change their epigenetic code, so they change the interpretation of that genetic

  • sequence so that they can actually do many new functions that they weren't doing previously.

  • One of the main questions in epigenetics is that the process is very plastic so a given

  • cell can actually change the way it behaves by changing its own epigenetic behavior. And

  • this can happen in even normal cells. And so a lot of people question whether these

  • epigenetic processes can really be selected for in a cancer cell and really stay stable

  • enough to drive the cancer cell to become initiated and then progress to very aggressive

  • forms. And that remains sort of an open question. And this research really tried to address

  • that in a very serious way.

  • What we found that was quite surprisingly actually is that the epigenetic changes were

  • almost as closely maintained as the genetic changes. And this is actually something that

  • I think will challenge a lot of notions that are out there that--that only genetic changes

  • are very stable and that epigenetic changes are too dynamic to really be selected for

  • in this way. This work really shows that the epigenetic changes can really also contribute

  • in the same way that genetic changes can. There's an implication for that. Mutations

  • that change a sequence in the DNA, we're actually finding there may not be as many

  • recurrent changes. Any given change is not so frequent in all different prostate cancers.

  • But interestingly, some of these epigenetic changes like DNA methylation, they can occur

  • in the vast majority of prostate cancers, the same exact change present over and over

  • again in many different people with prostate cancer. That's the making of an ideal biomarker.

  • Right; so you can actually use the same exact test on many different people and tell whether

  • they have cancer or not and in this case we're also finding markers that look like they might

  • be better for identifying those with aggressive cancer or not, in a way that you don't have

  • to have an individual biomarker for each person.

  • if you think about the genetic sequence in the cells, it's actually a vast volume.

  • So if you think about it as a book of letters, A, G, C, and T, it's six billion letters

  • long in a single cell. And that cell has to figure out which parts of those letters it

  • needs to use at a given time, and so one way it does that is it actually puts sticky notes

  • and little marks and bookmarks and--and little tabs on those pages so that it actually knows

  • to do something at a given time and--and sort of indexes it in that way. And those little

  • tabs and sticky notes we call epigenetic processes. And one such process is called DNA methylation;

  • it's sort of a sticky note which I put on as these little lollipops in this figure that

  • basically can mark these little fragments of DNA and we know that cancer cells can move

  • these sticky notes in ways that they shouldn't and put them in new places and erase them

  • from old places. And our goal is to try and study both the genetic sequence, but also

  • where these sticky notes were placed, these DNA methylation sticky notes were placed on

  • these DNA fragments.

  • And we had a technology that would help us do that and that technology is based on a

  • protein that actually exists in our cells called methyl-binding domain protein. And

  • this protein is actually very good at finding those sticky notes and binding to them. And

  • so we can use that protein to capture all the places in the genome where these DNAs

  • were marked by these DNA methylation marks and in a similar process just take all the

  • DNA, and process it, and analyze it by some of the latest innovations in micro-array technology

  • that allows us to interrogate the entire genome all at once.

  • Any time you look at the entire genome at once it's a real challenge because we have

  • six billion base pairs; it's this enormous space of information. And to really coalesce

  • it in a way that we can actually understand and sort of think about it is difficult. But

  • we finally think we have a nice way of really looking at all of the data in a way that can

  • be informative to us. And we call these the DNA methylation cityscapes or epigenetic cityscapes

  • of lethal prostate cancer. Each of these little blocks represent where a single chromosome

  • was sort of arranged into a neighborhood from the genome. So this red block here represents

  • a neighborhood of chromosome one; this one represents a neighborhood of chromosome two,

  • three, four, five, so on and so forth.

  • And overlaid on top of that is our actual cityscape where the data was plotted and what

  • we see is basically that some regions in the genome are really like skyscrapers, if it's

  • really tall on this cityscape is that it's very frequently changed in prostate cancer

  • compared to normal tissues.

  • Not only do we see the height of the buildings, we also see the color of these little buildings.

  • And we see that there's lots of buildings that are red and // those are clearly important.

  • They're things that occur very frequently in people and they're maintained in all

  • of the metastases from those people. And so there's genes like GSTP1 and APC that are

  • actually well known to be changed in prostate cancer that we see but we also see dozens

  • of other skyscrapers that are red that are giving us new biomarkers and new avenues to

  • actually pursue.

  • But what's interesting to me actually is that typically we would only use frequency

  • meaning how many people have a change as a measure of how important something is. But

  • that's not always the best measure because in some cases you might have something that's

  • not very frequent but for that one person it was very important. And we have examples

  • of that as well, like for instance, this MLH1 gene and the ESR1 gene, the arrows are pointing

  • to little huts, and those little huts are actually red and what that means is that very

  • few people had that change but when they did have that change every metastases from that

  • person had that change. That suggested that those changes really needed to be made upfront

  • in order for that to become a metastasis in that person. The fact that these changes were

  • maintained in every metastases suggested that it was really a driver of establishing metastatic

  • disease, and so we actually find numerous red huts across the cityscape as well.

  • Things that we may not be very interested in following up on any further are huts that

  • are white where there's really no maintenance across the individuals and across the metastases

  • within an individual but there's some small frequency or even lightly colored skyscrapers

  • like this one for instance where it really doesn't seem to be maintained across all

  • the mets from a given person.

  • And so we're actually following up on these types of findings further in another set of

  • human clinical specimens. This one is actually going to be a much larger set; it includes

  • 550 cases and controls of people that had very highly aggressive cancer versus not as

  • aggressive cancer in different ways, so either by pathological definitions or by functional

  • definitions like whether they recurred later on after therapy or not and--and we're wondering

  • whether the changes that we're finding in the lethal metastatic cancers from these individuals

  • are actually going to help us identify biomarkers and that's ongoing work that--that we'll

  • be hopefully finishing up in the next few months.

Integrative Analysis of Genetic and Epigenetic Alterations

字幕與單字

單字即點即查 點擊單字可以查詢單字解釋

B1 中級

致死性前列腺癌的遺傳和表觀遺傳學改變 (Genetic and Epigenetic Alterations in Lethal Prostate Cancer)

  • 21 4
    Kelvin 發佈於 2021 年 01 月 14 日
影片單字