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BRCA testing: what does it all mean?

Posted on 14 May, 2013 by Joe Dunckley

Hollywood actress Angelina Jolie has hit the headlines today, having told in the New York Times of her decision to have a double mastectomy to mitigate the raised risk of breast cancer that she inherited. Jolie described how doctors had told her that she had more than an 80% chance of developing the disease, and, although the genes that Jolie inherited are very rare, many readers might now be wondering what cancer risks could mean for themselves. Here at The Institute of Cancer Research in London, we’re a world leader in the genetics of cancer risk, and what to do about that risk once it’s identified is something we spend a lot of time thinking about.

Finding the genes

Although breast cancer is distressingly common — more than one in ten women will be diagnosed at some point in their lifetimes — and can strike any individual in any population, it has long been observed that some families are particularly badly hit by the disease. As Angelina Jolie herself described, there is a history in her own family, her mother having died at 56.

In the middle of the 20th century, as our understanding of genetics advanced, it became clear that this pattern of cancers running in families must be the result of one or more faulty gene being passed down the line. Soon a race was on to find the faulty gene or genes, and discover how and why the gene faults cause cancer. Competing teams of scientists developed new techniques to analyse the DNA, and used them to look for suspect sequences in families with histories of early-onset breast cancer. In 1994 an American team pinned down BRCA1, and a few months later BRCA2 was announced by a team led by Professor Mike Stratton, who was at the time working here at the ICR.

In the cell

Having discovered in the mid-1990s where exactly the BRCA genes are located on our chromosomes, scientists — including the ICR's Chief Executive Professor Alan Ashworth, fresh from the team that had identified BRCA2 — got to work on finding out what the genes do, and why they cause cancer when faulty. They discovered that both BRCA genes have roles in protecting DNA from damage. Specifically, they are part of the system which repairs breaks in the DNA strand — damage which typically occurs during cell division, when the DNA strands must be unpacked and copied. So without our BRCA genes, DNA damage would go unrepaired, and new mutations rapidly accrue to other genes — some of which then drive the development of cancer.

We inherit two copies of every gene — one from each parent — and so we have some insurance against faulty genes like these. However, with only one properly working copy of the gene, BRCA carriers are much more vulnerable: as random mutations hit our genomes over time, they are at risk of having their only working copy of the gene knocked out.

What are the chances?

Faulty BRCA genes are rare: only around 2 in every 1000 people carry a mutation. But what if you discover that you're one of the carriers of a faulty BRCA gene? What does this actually mean for your risk of developing cancer, and what are the options for dealing with that risk? Angelina Jolie was told by her doctors that her risk of breast cancer was more than 80% during her lifetime, compared with a typical lifetime risk of a little over 10%. But everybody's risk is different.

There is not just one type of fault that can hit each BRCA gene, but several. These faults vary in the extent to which they knock out the biological activity of the gene — preventing it from repairing DNA breaks — and so vary in their effect on cancer risk.

Additionally, hundreds of genes — not to mention environmental and lifestyle factors — interact to affect our risk of developing cancer. Although the BRCA gene faults have a very pronounced effect on cancer risk, many other gene variants can also affect cancer risk, and in combination with BRCA faults they may have synergistic effects. The breast cancer risks for carriers of BRCA faults are therefore typically in the 50%-85% range, depending on the exact faults identified, and which other factors can be identified.

But BRCA genes, despite their name, do not only affect the risk of breast cancer. Women carrying BRCA mutations have an increased risk of developing ovarian cancer at some point in their lifetimes — 1.4% of the general population suffer the disease, but the risk for carriers is typically in the 15-40% range. And BRCA carriers are at an increased risk for many other types of cancer, including colon, pancreatic, and prostate cancer.

Getting tested

Angelina Jolie discovered that she had a greatly increased risk of developing cancer after getting tested for the gene faults. She took the test because she knew there was a history of the disease in her family. The NHS offers BRCA testing, but limits the test to those who have similar reasons for concern. This is not just because the tests are currently quite expensive, but also because any form of testing is imperfect and has the potential to cause harm. In particular, all tests suffer from a small proportion of incorrect results. A false 'negative' result could give false reassurance, while a false 'positive' result would create unnecessary worry and stress. Either result could lead the recipient to take the wrong course of action. Since the great majority of the population — 998 in every 1000 — does not carry BRCA gene faults, testing indiscriminately would lead to many more harmful false 'positive' results, and so the test is limited to those who have an existing reason to suspect that they may carry gene faults.

Using the results

Angelina Jolie felt that with such a high risk of developing breast cancer, the odds were stacked such that surgery was her only option. Breast and ovarian surgery will greatly reduce the risk of cancer, although they cannot completely eliminate it.

But different BRCA carriers use their results in different ways. Their choices depend in part on the estimate of risk that they are given.

Rather than undergoing preventative surgery, some opt for regular monitoring, so that if cancer does strike it can be caught at an early stage when it is still easily treatable. BRCA carriers can opt for more frequent screening than the general population, and can take advantage of more detailed ultrasound and MRI scans in addition to the standard mammogram screening.

Another option not currently available to patients, but increasingly called for by cancer doctors, is preventative drug treatments. Trials have shown that breast cancer treatments like tamoxifen can also have a preventative effect, and could therefore be offered to those who are known to have an increased risk of the disease. However, tamoxifen does not completely eliminate the risk, and can have side-effects.

Cancer Research UK review these options for BRCA carriers on their website.

Fighting the genes

Knowing which gene faults increase our risk of developing cancer, and how they work, does not just enable us to develop tests and take preventative measures. At the ICR, we're also trying to use the knowledge to fight cancers when they do strike.

One particularly promising class of drugs that we have been working on in the Drug Development Unit are PARP inhibitors. These target BRCA-deficient cancer cells using a strategy called "synthetic lethality", exploiting the fact that the cells can not repair DNA strand breaks. The drugs attack the DNA, introducing partial breaks into the DNA strands. In healthy cells, where one of the two copies of BRCA is still functioning, these partial breaks are harmless and easily repaired. But in the tumour cells, the drugs soon cause the cell's copy of the genome to completely fall apart, forcing the cell to shut itself down. The drugs therefore meet one of the key demands of modern cancer treatments — targeting only the diseased cells. Several PARP inhibitors are currently progressing through clinical trials, including here at the ICR and The Royal Marsden's joint Drug Development Unit.


PARP inhibitors BRCA ovarian cancer
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