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Skip to 0 minutes and 15 secondsSo far this week, we've looked at different things in our environment which can cause a change in our DNA, and therefore make us more likely to develop cancer. But what about changes in our genes that we've inherited from our parents? Can these also make us more susceptible to cancer? Many of us will be aware from the media of high profile individuals who have undergone fairly drastic preventative surgery because they have been given a high risk of developing cancer. But how common is this? And how would someone know that they were at high risk? In this video we're going to investigate some of these questions.

Skip to 0 minutes and 53 secondsIt's important to realise that while all cancer can be called genetic simply because it's caused by changes in our genes, most cancer is not inherited. For example, only around 5% of breast cancers are caused by inherited changes in the DNA. Most of the cancer causing changes in our DNA occur in a specific tissue. But we all inherit some mutations from our parents, and these will be present in every cell in our body. In a relatively small number of people, these inherited changes are in genes relating to cancer.

Skip to 1 minute and 31 secondsSo we can see that for this child to develop cancer, a number of cumulative changes need to take place in his DNA. It can often take a while for this to happen, hence why cancer is more commonly seen at an older age. In the second child, you can see that they have inherited a mutation which predisposes to cancer in every cell in their body. Thus, it doesn't need so many hits for them to develop cancer, and it is more likely to occur at a younger age. We've already looked at some of the types of genes that these mutations might occur in.

Skip to 2 minutes and 8 secondsThey give the cell the ability to evade apoptosis, or cell death, grow and divide without the usual controls, stop it being able to repair damaged DNA, or give it the ability to acquire a blood supply or to invade other tissues. Having just one or two of these properties doesn't make a cell a cancer. Every cancer is the result of several mutations, each one of which gives the cell a growth advantage. Imagine that instead of needing to acquire all these mutations, someone was born with one of them already present in all their cells. That's what can happen in the cancer called retinoblastoma, which affects the eye.

Skip to 2 minutes and 49 secondsIn the non-inherited, or sporadic form, which is by far the most common, the cancer normally effects only one eye, and the average age for diagnosis is two years. However a small percentage of retinoblastomas are of the inherited type, which often affects both eyes and tends to be diagnosed at a much earlier age, typically around eight months. This inherited form of cancer is caused by mutations in the Rb gene. In week one, we mentioned this when we looked at Knudson's Two Hit Hypothesis. In people who haven't inherited any mutations in this gene, a cell needs two hits, or mutations, to knock out all activity of Rb.

Skip to 3 minutes and 33 secondsHowever, in people who have inherited a mutation in one copy, only one hit is required. Why is this gene important? Rb is an important regulator of the cell cycle, as we've seen in an earlier video. Inactivation of Rb protein leads to deregulation of another protein, called E2F, which in turn regulates transcription of genes involved in helping the cell move through the cell cycle, even though the conditions may not be ideal. Let's look at another form of inherited cancer, FAP, or Familial Adenomatous Polyposis. This occurs in around one in 10,000 individuals, and accounts for less than 1% of all colon cancer. The normal human colon has a very small number of polyps.

Skip to 4 minutes and 24 secondsEach polyp has a small chance of progressing to cancer. In FAP, the colon contains hundreds or thousands of polyps. Each polyp has the same chance of progression as a sporadic polyp, but there are so many polyps that one or more is almost certain to progress. The likelihood of developing colon cancer for an individual with FAP is around 100% by age 35 to 40. FAP is caused by an inherited mutation in the APC gene. We can look at the mechanism involved here. APC promotes downregulation of a protein called beta catenin, so if APC is not working because of an inherited mutation, this leads to beta catenin increasing.

Skip to 5 minutes and 13 secondsBeta catenin is able to move to the nucleus and activate other proteins which will help the cell progress on the pathway to cancer. So you can see how inactivating APC can lead to a cell gaining the properties that causes it to grow out of control. The final example we're going to look at is possibly the most widely known. It's the case of inherited breast cancers. There are several genes which have been implicated in familial breast cancer, including the most widely reported, BRCA1 and BRCA2. Somewhere between one in 100 and one in 800 people carry a BRCA1 or BRCA2 mutation, although this is slightly higher in certain populations.

Skip to 5 minutes and 56 secondsWoman who carry one of these mutations have a 40 to 80% lifetime risk of developing breast cancer, and a relatively high chance of developing ovarian cancer. This is considerably higher than the average lifetime risk of developing breast cancer for a woman who doesn't carry a BRCA1 or 2 mutation, which is around 10%. Men can also have a mutation in one of these genes, which also gives them an increased risk for breast cancer, although their risk is lower, at around 6%, because they have less breast tissue. BRCA1 and BRCA2 proteins have a role in repairing breaks in DNA.

Skip to 6 minutes and 37 secondsIf someone has inherited a mutation in one of these genes, they're not able to repair their DNA as efficiently as other people, and this makes them more prone to getting other mutations which can lead to cancer. We'll look at this a little more in a later step. Finally, what features in a family might suggest that someone has an inherited predisposition to cancer? Well, there are a number of things that doctors can look for, although none of these can say for certain. That's where genetic counselling is important.

Skip to 7 minutes and 10 secondsThings that can give clues includes a young age of onset of the cancer, several genetically related individuals affected by the same or a related cancer, two or more people with a rare cancer, three or more people with a common cancer, related cancers such as breast, ovarian and prostate cancer, or multiple primary tumours in one individual. If a mutation, for example, in BRCA1 or BRCA2 gene is found in a family, then individuals at risk can be tested for this mutation and offered genetic counselling. In the next video, we'll look at how genetic counselling is important in this process. We'll also look at some of the options available to individuals in this position.

Skip to 7 minutes and 56 secondsFor now, take a minute or two to review the points that we've covered in this video and to consolidate what you've learned.

Familial cancer syndromes

Dr Leah Marks outlines how inherited changes in our DNA can predispose us to cancer.

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This video is from the free online course:

Cancer in the 21st Century: the Genomic Revolution

University of Glasgow