Inherited predisposition to breast cancer

Published on September 3, 2014   53 min

Other Talks in the Series: Molecular Genetics of Human Disease

0:00
My name is Professor Diana Eccles and I'm a professor of cancer genetics at the University of Southampton and have a clinical practice in the Wessex Regional Genetic Service.
0:14
Breast cancer is very common worldwide, and the incidence varies quite markedly between countries. In Western Europe through to Asia, as you can see from the graphs here, mortality is less variable, and this depends a little bit on the different sorts of breast cancer that occur in these countries, but also of course on early diagnosis and treatment.
0:42
There are many risk factors that are known for breast cancer, and increasing age is a very typical risk factor for breast cancer and many cancers in the Western world. Late age at first birth is associated with an increased risk for breast cancer, with a threefold increase in risk for women having children after 30 years of age compared to women having children below 25 years of age. And of course, women are having fewer children in the Western world now. Excessive iradiation of the chest in the teenage years is known to be associated with an increased risk of breast cancer, and the evidence from the Hiroshima bomb also indicates that radiation exposure increases breast cancer risk. Replacement of oestrogen at the natural menopause also increases breast cancer risk, but particularly if it's given with progesterone. Oestrogen only seems not to increase the breast cancer risk significant. Obesity is clearly a risk for postmenopausal breast cancer but less so for premenopausal breast cancer. However, in all ages it increases the risk of dying from breast cancer. Early onset of periods and late menopause also increase the duration of exposure to the oestrogen, and both of those are risk factors that increase breast cancer incidence. And then the main breast cancer risk factor that we're concentrating on in this lecture, of course, is a family history of breast cancer. But independent of that, and also very heritable, is the mammographic density.
2:17
There are many genes that predispose to breast cancer, and there's a relationship between the likelihood that breast cancer will develop when carrying a particular gene mutation and the population frequency. So the higher the penetrance, the higher the risk of breast cancer. If you've got a gene mutation, the lower the frequency in the population. So there were a few known high penetrance genes that are relatively rare in the population. There are larger number of moderate penetrance genes-- in fact, a unknown number of moderate penetrance genes-- and there are a large number of low penetrance high frequency
2:57
Genes do not act in isolation, they very much interact with each other and with the environment. And in a model of this, you can see that genetic risk can go from low to high and the environmental risk can go from high to low. And genetic and environmental risks work together. All of the breast cancer cases-- if you imagine that those are represented by the lower curve there and all of the stars represent genetic risk factors, with the red star being for example the BRCA1 or P53 gene representing a very high genetic risk. So all of those lower penetrance genes, you may have several of those before you develop a breast cancer, and you may have several of those and not develop a breast cancer. And each of those lower penetrance alleles is balanced by genes that reduce the risk of a breast cancer. It is possible to carry, for example, a BRCA1 or BRCA2 gene and many lower penetrance alleles, and this would bring down the likelihood of developing a breast cancer, so modify the genetic risk.
4:02
The distribution of breast cancer risk can be plotted relative to the population average of one, and this is a graph that was drawn by Sarah Sawyer at the Peter Mcallum Cancer Institute in Melbourne. Plotted on the graph, the distribution of risk, which you can see there's a very high tail heading up there based on first degree relatives and then for much younger first degree relatives. So the women who drink alcohol on a regular basis, two standard drinks a day, the relative risk increases to about 1.15, 1.2. And then for obese women the risk increases again to about 1.2, and those two things would act together. And then with a first degree relative, the increase in risk is heading towards twofold. And with a young first degree relative it exceeds twofold and so forth. Now the relative risk of a BRCA1 gene can be much higher than that, but all of those factors would also be relevant in increasing the risk for a BRCA1 gene carrier.
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Inherited predisposition to breast cancer

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