Hi everyone, welcome back to Lecture 4J of Useful Genetics, where we're going to talk about how somatic mutations cause cancer. We'll talk about how cancer cells differ from normal cells, and how cancer begins with mutations that cause cells to grow when they shouldn't. We'll talk about mutation rates in cancer cells, and about the very complex genetic structure of tumors. Now, Here's a diagram of how normal cells behave.
They stop growing. They're very well behaved. They stop growing when they're told to. They don't steal the blood supply to get more nutrients, more oxygen than is their fair share. They can't grow forever.
They only grow when they're given signals to tell them to grow. And they politely die when they're not needed. And finally, they stay put.
They don't wander around. body moving into new places. Cancer cells, in contrast, do all these things wrong. They ignore signals to stop growing, and very often they even synthesize their own growth signals, so they don't have to pay any attention to signals from other cells. Often they can grow forever.
They ignore signals telling them that it's time to die. They... send out signals that actually steal the blood supply away from other cells, so the tumor cell gets more than its normal share of oxygen and of nutrients, and they wander.
They both, depending on the tumor type, they can crawl away into nearby tissues, that's invasion, or they can break loose and start to grow in totally new locations. That's called metastasis. So all of this happens because cancer cells have mutations that cause them, a cancer cell arises with a mutation causing it to grow when it shouldn't. But once these mutations exist, cancer cells then go on to change by a kind of natural selection.
Mutations arise, and depending on the effects of these mutations, these mutant cells persist or are lost from the tumor. And it's... like natural selection, as if these cells were an independent species, not the trustworthy, well-behaved parts of our bodies that we want our cells to be. It's been said that no two tumors are alike.
Each has a web of mutations. Typically, they can have thousands of mutations, different mutations in different tumors, different mutations in different parts of the tumor, as you'll see. So here's just a little schematic.
Think of this as a single cell, a somatic cell, that has acquired a mutation that causes it to grow, and it shouldn't. I'll indicate this initial cell with the mutation with a little red star. Now, as the cell grows and divides under the influence of its first mutation, it's undergoing more mutations, creating descended cells that have different genetic properties.
Different mutations happen at different times and in different places. And the whole population of cells gradually comes to consist of many different variants descended from the original initiating tumor cell. Now, this occurs not just because of mutations happening at the normal rate, but because cancer cells have higher mutation rates than normal cells. They make more genetic mistakes.
and we can tabulate the ways they go wrong. For one thing, DNA damage occurs more often in cancer cells, partly because they're growing fast, partly because they're growing under conditions that are sub-optimal, and the damage that does happen is often not repaired. Then the process of DNA replication itself loses genetic control. So it's not well synchronized, different parts of the genome are replicating at different times.
Cells have what are called checkpoints, various regulatory processes that serve to ensure that normal cells don't go on to divide until they've replicated all of their DNA and there's no damage in the DNA. Cancer cells lose these checkpoints and so they go on to replicate. even when they're not ready, and as a consequence, they very often lose or gain whole chromosomes when the cells divide because DNA replication and repair hadn't been properly completed before cell division began because the checkpoints were being ignored. So this means that cancer cell populations, the descendants of the initiating cell, they evolve and accumulate genetic changes that can in particular improve their growth or drug resistance. So natural selection eliminates any cells that have mutations that make them grow more poorly, but it favors mutations that increase the cell growth or mutations that make the cells resistant to any drugs that the patient might be treated with.
So medical goals are to use chemotherapy to block the effects of these mutations, block the growth promoting in other behaviors, and at the same time prevent more mutations from occurring in the hope of keeping the cells genetically stable so that they can be killed by chemotherapeutic drugs. But these goals are very difficult to achieve because For one thing, every tumor is unique. Even though, for example, many breast cancer tumors start with mutations in one of two particular genes, as they evolve into a large population of tumor cells, they acquire many different mutations.
Different tumors have different mutations. Second, the genetic changes arise at random. We can't predict what changes will arise or when they'll arise.
We can make some predictions about the phenotypic consequences of particular mutations if they happen. And finally, even for the cases where we can predict phenotypic consequences of particular mutations, those predictions depend on the mutation being in a stable genetic background. But within the tumor cell, there's many mutations in each cell, so that the mutations, different cells, even if they carry one mutation that's the same, they'll carry many other different mutations, causing them to respond differently to changed growth conditions or to chemotherapy drugs.
So here's one example of a study. This was published a couple years ago. This was a patient who had what's called renal cell carcinoma.
They had cancer in their kidney. And that tumor that began in their kidney. had undergone metastasis.
Cells had broken away from the initial tumor and formed new tumors, some on the kidney, some on the chest wall, some in the lungs. What the researchers did was they took samples of tumor tissue from different parts of the primary tumor and from different metastases and they sequenced their genomes to look for mutations. And they found, just in the limited sample that they sequenced, they found 101 non-synonymous point mutations. Those are point mutations that changed the amino acid sequences of proteins. They found 32 INDELs, insertion and deletion mutations.
Some of these mutations were common to all of the samples and were probably mutations that arose early in the primary. tumor. Some of them were only in part of the tumor, representing sectors that grew from particular new mutants. Some were only in the metastases.
Some of the cells in the tumors were tetraploid. They had four copies of all their chromosomes, so they clearly had a cell division that had totally failed. And many of these mutations are likely to be partly responsible for the increased cell growth. of the tumor cells.
So what kinds of genetic changes can create the initial tumor cell? Well, one kind, these tie back to the mutations that we discussed in the previous lecture about regular interactions in regulatory mutations. They can be proteins whose job is to stimulate cell growth. These are like the GO gene that we described previously. And what's required to turn for a mutation in these cells, to turn a cell into a cancer cell, is that the mutation activates the gene.
It turns on the promoter of the gene, so the gene is expressed when it normally wouldn't be. Another kind of protein, another kind of mutation, is mutations in proteins that suppress cell growth. These would be like the stop gene that we described previously, and the kinds of mutations that would cause Tumor cells is mutations that lost the function.
They're not activating mutations. They're loss of function mutations in stop genes. Tumor biologists have names for these kinds of mutations. They call mutations in proteins that stimulate growth.
They call these genes proto-oncogenes because when they're activated they become oncogenes, genes that cause tumor behavior. The stop genes they call tumor suppressor genes because when they're working they prevent tumors from forming. Finally there's a third class of mutations that can create an initial tumor cell or contribute to its creation and these are mutations in the proteins that tell cells when to die.
This telling cells when to die occurs as part of a specific regulatory process with a very peculiar name, apoptosis. and this is the programmed cell death that normally occurs in many of our cells and that fails to occur in many tumor cells. Now here's a question tying together ideas of dominance and recessiveness with ideas of protein functions controlling cell growth.
Is a loss of function mutation in a protein that normally suppresses cell growth, likely to be dominant or recessive to the normal allele? The answer is it's likely to be recessive. This is a stop protein, and it's going to, having only one functional stop protein, is likely to be enough to still control the growth of the cell. So, So what we've done, we've talked about cancer and the great genetic diversity of cancer.
Different types of cancer are caused by mutations in different kinds of cells. They cause the cells to grow when they shouldn't. So cancer is fundamentally a genetic disease caused by somatic mutations. The other cells in the body, the cells that aren't part of the tumor, are normal.
They have not got the mutations that cause cancer. Although, as we'll see in the next lecture, the other tissues in the body may carry mutations that predispose to the development of cancer. So coming up next, we're going to talk about cancer risk factors.
I hope to see you there.