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Skip to 0 minutes and 15 secondsFor decades, scientists have been trying to find out what causes cancer. In this video, we will see that data for cancer incidence can be interpreted to show that cancer is the result of a series of steps that may occur over a long period of time. Most people are aware that exposure to radiation and chemicals can lead to cancer. We know that these agents can cause damage to our DNA and, therefore, mutations in our genes. But we also know that cancer may not appear until several years after exposure to these DNA-damaging agents. Why is this? Cancer is typically a disease, which affects older individuals. The risk of cancer increases as we age.

Skip to 1 minute and 0 secondsData like this led scientists in the 1950s to predict a multi-stage model for cancer in which six or seven hits were required to produce the cancer. Let's look in more detail at how this works. As we get older, we start to accumulate damage to our DNA. Some of this damage-- shown by the circles-- may represent a step on the pathway to cancer. However, because it takes around six hits before cancer occurs, we do not see many cases of cancer during early adult life and middle age as shown in the graph on the right. But as the damage accumulates, more and more cases of cancer are seen in the population.

Skip to 1 minute and 46 secondsAnd we see the typical rapid increase in cancer cases in the older population. To understand what is happening, we need to look at the cells. We start with a group of normal cells, which are proliferating in a controlled way. Suppose one cell sustains a mutation that makes it grow and divide a little bit faster than the other cells. Because we have a group of cells that are proliferating faster, they are more susceptible to future damaging events. Each successive mutation generates a new subclone of cells that have greater abilities to survive and to increase in number. They have escaped the control processes that normally regulate proliferation of cells in our body.

Skip to 2 minutes and 36 secondsThe faster-growing clone of cells may lead to a visible lump, but may still be a benign growth or benign tumour that could be removed by surgery, one reason that it is important to detect cancer at an early stage. However, some cells may also acquire additional changes that make them invasive and allow them to break free of the original tissue to spread to other sites in the body where they may form metastases or secondary cancers. So what are the genes that are the targets of these mutational hits? Some of the first clues came from the study of a childhood cancer.

Skip to 3 minutes and 21 secondsIn contrast to the cancer types like colon, lung, and breast cancer that usually affect adults in later life, some types of cancer typically occur in young children. Retinoblastoma is one of these cancer types. Cases of retinoblastoma can be classified into two groups-- sporadic and familial. In sporadic cases, which represent about 60% of retinoblastoma cases, other family members are not normally affected. The cancer affects one eye only and at an average age of about 2 years. In contrast, in familial cases, not only are other family members affected, but retinoblastomas are often found in both eyes, and the age at onset tends to be younger than in sporadic cases.

Skip to 4 minutes and 17 secondsIt was from data like this that Alfred Knudson in 1971 developed his two-hit hypothesis for tumour formation.

Skip to 4 minutes and 28 secondsFrom the earlier video on the normal cell, you will remember that each of our cells carries two copies of our genome in the nucleus. One copy of each chromosome inherited from our mother and one copy from our father. Therefore, each gene is present in two copies. We will consider one of these genes, which is called RB for retinoblastoma. We will consider first sporadic retinoblastoma. The majority of the population will inherit two active copies of the RB gene. As a result of mutational damage to a cell in the retina, one of the RB copies in that cell may become inactivated, but the cell has a second copy of RB to carry out the normal function.

Skip to 5 minutes and 20 secondsHowever, if a mutation now occurs in the remaining RB gene of that cell, the protective function of RB is lost, and it is now possible for a cancer to develop. Mutational events are rare so it is apparent that two mutations occurring in the same cell will be very rare. Of the thousands of cells in the developing retina, several may sustain damage to one RB gene, but it will be rare to get the second copy of RB mutated in the same cell. This is why retinoblastoma is uncommon in the general population.

Skip to 5 minutes and 58 secondsHowever, if a child has inherited an RB mutation from the egg or sperm contributed by one parent then every one of the thousands of cells in the developing retina of that child already has this mutation. It now only needs a single hit in the active RB gene in any one of these cells to generate a cell with no functional RB. Of the thousands of cells in each retina, it is expected that mutation of the functional RB copy with occur in several cells. Therefore, a child with an inherited RB mutation will almost certainly develop retinoblastoma cancers, and quite likely in both eyes.

Skip to 6 minutes and 46 secondsThe RB gene is one of a group of genes whose normal functions protect against cancer, termed tumour suppressor genes. In our genomes, there are many genes whose products have tumour suppressor activity. RB is just one of these. If one copy of a tumour suppressor gene is inactivated, the other can still function to prevent the cells from becoming cancerous. During progression to cancer, it is commonly found that both copies of a particular tumour suppressor gene will be inactivated, and cancer may develop.

Skip to 7 minutes and 24 secondsSo to summarise, cancer is the result of a series of changes, which are steps on the pathway to tumour formation. Exposure to DNA-damaging agents increases the likelihood of each step. Mutations in genes involved in processes, such as cell survival, cell proliferation, and cell motility can lead to the development of cancer. Some of our genes act as tumour suppressors. And for a cancer to develop, it is necessary to destroy both copies of one gene, as Knudson proposed in his two-hit hypothesis. Cancer has an earlier onset if one mutation is inherited, as in the case of retinoblastoma.

Skip to 8 minutes and 11 secondsMany other cancers, like colon cancer and breast cancer, also have inherited forms, which tend to have an earlier age of onset than sporadic cancer since the first step on a pathway to cancer has already occurred in all cells. It is important to recognise that there is more than one different series of damaging events by which a cell may become cancerous. In future videos, we will look in more detail at what genes are involved and at the regulatory networks that are disrupted in cancer cells. We will see how the detailed understanding of these mechanisms gives rise to hope for improved treatment of cancer in the future.

Cancer is a multistep process (9.01)

Dr Maria Jackson introduces us to the idea that cancer is not due to a ‘one-off’ event, but an accumulation of damage occurring during a lifetime.

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This video is from the free online course:

Cancer in the 21st Century: the Genomic Revolution

University of Glasgow

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