Tracking down the BRCA2 gene

In part one, we told the story of Cancer Research UK’s involvement in the race to identify BRCA1 – the first known breast cancer gene.

Although this was a very important discovery, it wasn’t the end of the story. Along the way, researchers had discovered evidence suggesting that there had to be at least one more gene out there.

Here we look at how our scientists revealed the identity of the second breast cancer gene, BRCA2, and what the discovery of both these genes means for cancer patients and their families.

The next hurdle – BRCA2

As we mentioned in part one, although BRCA1’s discovery was incredibly exciting at the time, researchers found that it wasn’t responsible for every case of inherited breast and ovarian cancers.

Research showed that faults in BRCA1 accounted for most families with many cases of both breast and ovarian cancer that set in at an early age, and just under half of all families affected by multiple breast cancer cases. But the gene wasn’t implicated in any families affected by both male and female breast cancer.  The hunt was now on for the next breast cancer gene – “Breast Cancer 2”, or BRCA2.

Professor Mike Stratton led the team that tracked down BRCA2

The main hurdle in the search for this gene was cleared in 1994 by an international team led by Professor Mike Stratton at The Institute of Cancer Research. With funding from Cancer Research Campaign (Cancer Research UK’s predecessor), the Medical Research Council and others, researchers analysed DNA from 15 families from around the world affected by early-onset breast cancer that wasn’t related to BRCA1.

Using painstaking genetic techniques, the researchers pinpointed the location of BRCA2 to a region on one end of human chromosome 13 – a region known to contain a number of different genes. As with BRCA1, scientists around the world then raced to pin down which one of these was BRCA2.

Professor Stratton – along with a team that included several other Cancer Research Campaign-funded scientists – was the ultimate winner. They revealed the identity of BRCA2 in a paper published in the journal Nature at the end of 1995.

Using DNA samples from a set of Icelandic families affected by multiple cases of breast cancer, Stratton and his team had narrowed down the possible location of BRCA2 to a relatively small region of DNA within chromosome 13. Next, they figured out which bits of this region were likely to code for proteins (genes), and set about reading the DNA sequence of these potential genes in members of 46 families affected by breast cancer unrelated to BRCA1.

In particular, the researchers were hunting for mistakes in the DNA sequence that would stop the sequence being ‘read’ by a cell.  After poring over thousands of DNA ‘letters’, the researchers spotted ‘stop signals’ in the same gene in 3 people from different families.

Could this be the elusive BRCA2?

To confirm BRCA2’s identity, the scientists pulled together the full DNA sequence of their prime suspect. Luckily, this task was made easier by the Human Genome Project – an international consortium of researchers sequencing the entire human genome – who had just published a draft version of the DNA sequence from the end of chromosome 13.

The researchers patched together the sequence of the entire gene and compared it to the DNA of people from families affected by breast cancer.  They found mistakes in the gene in members of several different families, including those affected by male breast cancer. But they didn’t see any faults when they looked at DNA from over 500 healthy women.

This was enough evidence to confirm the identity of the mystery gene as BRCA2.

Moving forward

Since the BRCA genes were identified, they have come under intense scientific scrutiny. We now know that around 1 in 1,000 people carry a fault in one of the genes, and that around 2 in every 100 women with breast cancer have a faulty version of either BRCA1 or BRCA2.

Carrying a faulty version of a BRCA gene means a woman has a roughly 80% chance of developing breast cancer in her lifetime – as opposed to around a 12% chance in the general population, roughly 1 woman in 8 – and more than a 50% chance of getting ovarian cancer.

In 1995, our funding allowed scientists at The Institute of Cancer Research to show that BRCA1 faults were more common in younger women who develop breast and ovarian cancer. We now know that faulty BRCA2 is also linked to male breast cancer as well as prostate and pancreatic cancers, and in 2008 our scientists revealed how specific faults in BRCA2 can affect how a patient’s cancer responds to treatment.

Life-saving knowledge

People with a strong family history of breast and ovarian cancer are now able to have genetic testing to find out whether they carry a faulty version of BRCA1 or BRCA2. If they do, then they may wish to take steps such as regular breast screening, surgery to remove their breasts or ovaries, or preventative drugs to help reduce their chances of getting cancer.

And in 2009, a baby girl was born as a result of an IVF procedure that ensured she would be free of the hereditary BRCA1 fault that had led to her father’s family being haunted by breast cancer for generations.

We also now know that BRCA1 and BRCA2 aren’t the complete story when it comes to breast cancer genes. Although these 2 genes have the strongest effect on breast cancer risk, researchers have since discovered many more genes that can influence the chances of getting the disease – and our scientists have been at the forefront of this work.

For example, in 2002, Cancer Research UK-funded scientists in Cambridge and at The Institute of Cancer Research led a team that discovered a new breast cancer gene called Chek2.  And in 2003, a different team of Cancer Research UK-funded scientists in the city tracked down EMSY – a gene that proved to be the missing link between BRCA2 faults (which are only found in hereditary cancers) and randomly-occurring (sporadic) breast cancers.

Cancer Research UK scientists are also leading the way in discovering the more subtle variations in our DNA that have a smaller impact on individual cancer risk.  They were part of a ground breaking 2007 study that found 5 new gene regions linked to breast cancer, and in 2010 they found 5 more. And in 2012, scientists at our Cambridge Research Institute found the first new ‘cancer accelerator’ oncogene in five years, which is also implicated in up to 4,000 cases of breast cancer every year in the UK

This genetic knowledge is starting to work its way into clinical reality. Our researchers are developing sophisticated computer models – such as a programme called BOADICEA – that can help to predict an individual woman’s risk of breast cancer based on her genetic heritage and family history.

And they’re also calculating how genetic information could help to make breast screening more effective by focusing particular attention on women at highest risk of the disease.

From the lab to the clinic

Hundreds of detailed lab studies have revealed what BRCA1 and BRCA2 look like, what they do in cells, how they work, and the other genes and molecules they interact with.  We now know that they help cells repair damage to their DNA, helping to protect us from cancer. If either BRCA gene is damaged or faulty, then the cell can’t repair this damage, increasing the chances of cancer developing.

This finding led to the development of exciting new experimental cancer drugs known as PARP inhibitors, which exploit this genetic ‘Achilles’ heel’ in cancer cells lacking BRCA.  Our scientists, and other groups around the world, are now testing PARP inhibitors in clinical trials with promising early results.

Across the globe, scientists continue to pore over BRCA1 and BRCA2, trying to understand what makes them tick and how we can use this knowledge to beat cancer.

Just in the past year or so Cancer Research UK scientists have discovered how BRCA1 may be linked to so-called ‘triple negative’ breast cancer, unravelled the complex three-dimensional structure of BRCA2 on an atomic scale, and figured out a molecular ‘volume control’ that helps to determine whether a woman carrying a faulty version of BRCA1 will go on to develop breast cancer.

But there are still plenty of mysteries that need to be solved. For example, it’s still not clear exactly why BRCA1 and 2 faults only cause a relatively small range of different types of cancer – breast, ovarian, prostate and pancreatic – when the faulty genes are found in every cell of the body.  And although the results from the PARP inhibitor trials look good so far, the drugs don’t work for everyone.

Discovering the BRCA genes was just the start. Cancers caused by BRCA faults tend to occur in younger people, and are harder to treat. We urgently need to continue to turn the knowledge gained through research into more and better ways to treat people with cancer. Our researchers have made great strides in the past and – with the help of our supporters – we can make even more progress in the future.

Kat