This week we're going to be talking about cancer epigenetics. And so, during the week, we're going to bring in much of what you've learned in the first five weeks of the course to try and think about what goes wrong in cancer epigenetically, and what clinical implications does this have. So we know a lot about what aberrations are found epigenetically in cancer now, at least in terms of DNA methylation. We know something about the histone modifications that go awry along with a little bit about nuclear architecture and noncoding RNAs. So, throughout the next few lectures what we'll do is we'll go through each of these abnormalities. And think a little bit about they mean in terms of the clinical outcome. So, with any abnormality that we learn about in terms of cancer epigenetics, they have the potential to be useful diagnostically, prognostically, or potentially even being able to be manipulated for therapy. So before we start to think a lot about this, let's just refresh on what cancer is. So cancer has a series of hallmarks. The ones on this image that are shown with a rectangular box are the more historical ones that have been discussed. Say, for example they have evasion from growth suppression. You have sustained proliferative signalling. You resist cell death. Because the cancer cells are very actively dividing, they need to induce angiogensis, in other words be able to have blood vessels bring in more nutrients. They need to activate invasion and metastasis, so you get further than that primary tumour, and they need to be replicatively immortal. So these are the traditional hallmarks of cancer, but in addition to these, more recently, additional hallmarks have been described. The emerging hallmarks are avoiding immune destruction and deregulating cellular energenetics. And enabling characteristics, such as inflammation and genomic instability and mutation. So while originally cancer was thought to be an accumulation of genetic mutations and that these genetic mutations would influence each of these hallmarks of cancer. We now understand that it's not just a genetic disease, but rather there are genetic abnormalities partnered with epigenetic abnormalities. And really these epigenetic abnormalities, depending on where they occur in the genome, can have a consequence, and influence all of these hallmarks of cancer. And so you can think of cancer, rather than being just a consequence of genetic mistakes, but rather a consequence of both genetic mistakes and epigenetic mistakes. So in the simplest possible terms, cancer really involves activation of oncogenes, and these might be the genes that are involved in growth promotion, so allowing immortality and allowing the cell to just continue dividing rapidly. And inactivation of tumour suppressors. And the tumour suppressors are the genes that would normally be able to make the cell die or decrease the proliferation. So by activating oncogenes and inactivating tumor suppressors in combination, this results in a cancer. So how do you actually enable this activation and inactivation? Well, this can happen both genetically or epigenetically. So genetically you could over express oncogenes by amplifying them, so having multiple copies of the same gene for example. And you could inactivate a tumor suppressor by mutating it, or deleting it entirely. But epigenetically we know that you could activate an oncogene by allowing it to be expressed because of the epigenetic signatures found at that oncogene. And indeed you could inactivate a tumour suppressor by epigenetically silencing the tumour suppressor, and all of these things indeed do occur in cancer. So I guess then what I've said is that you have both genetic abnormalities and epigenetic abnormalities in cancer. So what's the interplay be the two, which is the chicken and which is the egg? Well at the moment we still don't really understand which happens first, so what's the cause versus the consequence? But rather we know that genetic mistakes can result in epigenetic abnormalities, and equally epigenetic mistakes can contribute to genetic abnormalities. So in the coming years, I'm sure that it will begin to be teased at what the interplay is and what may actually be the original driver in tumor genesis. But as mostly happens with biology as we learn more and more about these processes, it's highly likely that this will be different in each individual tumour type and perhaps each, and in each individual. So while we don't yet understand about the cause versus the consequence for these genetic and epigenetic mistakes, that are made in cancer, although this is a really fundamental question to ask, it doesn't influence our ability to take advantage of the understanding about these epigenetic mistakes that are made in cancer for therapy or for clinical use. So as I said, we can use these for diagnosis. And, I'll explain what I mean by that. How it is that we can use these epigenetic mistakes to actually diagnose cancer, in the first place. We can use them to look at prognosis, in other words, what the outcome for the patient is likely to be. Can we predict how long they may survive or predict what treatment might be best. Or can we target these epigenetic mistakes therapy? So one of the reasons that these mistakes, these epigenetic mistakes, are clinically relevant and are useful to look at is because they progress over time. So here I'm just showing you an image of what happens with DNA methylation. So, at the top you can the different types of tissue. Starting with the normal tissue, and progressing through to achema that is undergoing metastasis and is invading the blood tissues of, where the cells can then passage to another site. But what we know about is that the global level of methylation as shown here, decreases as you progress from a normal tissue through to a metastatic tissue. But at the same time, methylation at some CpG islands becomes more dense. And so because of this change as you go through from normal tissue, to hyper-plastic tissue to neoplasia and then invasive tissue, because we see this progression in terms of these DNA methylation markers of cancer, it means that you might be able to use, or you can use, these markers to be able to detect whether perhaps there's a tissue that is in fact cancer, compared with normal. Or indeed perhaps whether or not it's metastatic, and this is all very important in terms of clinical outcome. So with this general introduction to how we can think about cancer epigenetics and how we might be able to use these pieces of information. In the subsequent lectures we're going to go through each of these epigenetic abnormalities with the most detail on DNA methylation. We'll think about DNA methylation abnormalities and what the consequences are and what it means for diagnosis and prognosis. We'll think about, a small amount about each of the other aberrant epigenetic marks. And then at the end of the week, we'll begin to think about how this can be used therapeutically. How we can actually begin to, and what has begun in terms of epigenetic therapies for cancer.
