Today we introduce a new monthly series of interviews with genes. Each month a different gene will tell us a little bit about themselves and how and why they are linked to human disease. This month BRCA2 is in the spotlight.
Why are you called BRCA2?
My full name is ‘BRCA2, DNA repair associated’ though it used to be ‘breast cancer 2’, and before that ‘breast cancer 2, early onset’. The ‘BR’ stands for breast and ‘CA’ for cancer and the 2 refers to the fact that I was the second gene to be discovered through the study of breast cancer families.
Humans discovered my existence in 1994 and my full sequence in 1995. This was before the human genome sequence was available, so the scientists had to work out my sequence from scratch. It was a painstaking process. At the time, the only thing people knew about me was that my genetic variants were ‘linked’ to breast and ovarian cancer in the families they were studying. This means they were present more often than possible by chance. Why this was so, or what I did, or why the variants increased the risk of cancer was not known. I was named after breast cancer, because it was the only thing known about me.
Now there are 1000s of research papers about all the wonderful things I do to keep people well and my name was changed to reflect the things I do, rather than what happens when I am not in tip-top shape.
Incidentally, my name should be pronounced ‘B-R-C-A’ not ‘BRACA’. I say this purely for historical accuracy, not with any expectation that people will change. I gave up hope of that long ago.
How do you spend your days?
I have a very important job. The protein I code is part of an expert team that repairs damage to DNA. DNA gets itself damaged all the time, in all sorts of ways. Cells have lots of different proteins working in lots of different ways to repair the damage. I specialise in repairing double-strand DNA breaks, i.e. breaks to both the DNA strands. We’ve come up with a really neat way of doing this which uses a template of the correct sequence as a guide for the repair. It makes the repair much more accurate than just sticking the broken DNA ends together (which some of my colleagues do).
Do you have any friends we should know about?
Well I guess I have to mention BRCA1. Everyone has heard about her, particularly after she got celebrity endorsement from Angelina. People assume that because she is number one and I am number two, she is more important than I am. This is not true. I am much bigger for start. She is only 1863 amino acids. I am a whopping 3418. She just happened to be discovered first.
Even though we have similar names, we do different things, we look different and we don’t hang out together much. I have much closer colleagues like PALB2 and RAD51, and all my mates from the Fanconi complex. We’re a really tight unit.
How are you linked to human disease?
Everyone has two copies of me, in every cell. About 1 in 200 people are born with a genetic variant that causes one copy to not work. The second copy does a valiant job fixing DNA breaks so this doesn’t cause too much trouble. But sometimes the second copy gets lost or gets altered so it doesn’t work either.
Cells in which I’m not able to work at all struggle to repair damaged DNA. More and more genetic changes start to accumulate. If one of these causes the cell to grow uncontrollably it turns into a cancer.
When I am working well I am particularly good at preventing breast and ovarian cancers happening. So when I am not able to do my job properly these are the cancers that tend to occur.
Very, very rarely a child is born with genetic variants in both of my copies that stop me working in every cell. Sadly, this causes severe problems for them, including a very high risk of cancer in childhood. Usually they die from cancer before they are an adult. The condition is called Fanconi anemia subtype D1.
What are you most excited about in genetic medicine?
People found out nearly 25 years ago that I need to be fully fit to help keep breast and ovarian cancer at bay. Knowing if a cancer is due to my not working is important in deciding which treatments to give. You can also prevent cancers from happening if you know I’m only functioning at 50% capacity before cancer has occurred.
So many cancers could have been prevented by now, if genetic testing had been more available. But it used to be too difficult and too expensive. Now new sequencing techniques have finally made it quick, easy and affordable to do gene testing. It’s so exciting. Finally cancer patients and their relatives and anyone in whom I am not working well enough, will be able to get tested. This will let them make better informed choices about cancer treatment and prevention.
What are you most concerned about in genetic medicine?
People often don’t understand that I have lots of minor variants that don’t cause any harm and don’t increase their risk of cancer. They often seem to think that any variant they haven’t come across before can cause cancer. Then they can over-react and start doing extreme things, like having unnecessary major surgery.
Sometimes I find myself wishing I’d never been discovered at all. If people could use the information about me appropriately they would do so much good, and help so many people. But you have to know what you are doing and be calm and considered, otherwise you could end up causing more harm than good. I’m really anxious about it.
Tell us a surprising fact about you?
I’ve been the subject of a famous lawsuit. It went on for nearly 20 years and ended up in the US supreme court. A company called Myriad genetics patented me and BRCA1 and tried to stop anyone else doing genetic testing. I found it particularly galling because Myriad didn’t even discover me, I was discovered by a British group, led by Sir Mike Stratton.
I never imagined it would take so long to overturn the patent – it was an extraordinary journey. Someone should make a movie about it. But finally, in 2013, The US supreme court unanimously ruled that “A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated,” and the patents were overturned. This meant other companies in the US could finally test the BRCA genes. Many more people have been able to get testing since. It’s made me so very happy.