A breast cancer cell. Credit: LRI EM Unit.
25 years ago, a team of our scientists were celebrating. Their risky strategy had paid off.
“You look back and you do wonder about how we decided to do this, and basically it was because we believed that it was better to do high-risk research that potentially would be important,” recalls team leader Professor Mike Stratton, “but with the full knowledge that, perhaps, the gene didn’t exist.”
But exist it did – in fact, the team had just pinpointed the location of what would become one of the most famous ‘cancer genes’ known to science – BRCA2.
And in the process, they opened the door to ways to give people more certainty about their risk of cancer and paved the way for new and better treatments.
The hunt for BRCA2
The hunt for ‘breast cancer’ genes began in the 1940s, when researchers discovered that the disease could occasionally run in families. It became clear in the following years that these clusters of breast cancers in families were caused by faulty genes.
But pinpointing the specific genes responsible would take decades. We’ve written before about the race to discover the first breast cancer gene, dubbed Breast Cancer 1 or BRCA1, which was found to sit on chromosome 17 in 1990 by a team of US researchers.
“Much of the focus after BRCA1 was located was on clarifying that discovery, confirming it and narrowing down exactly where BRCA1 was,” says Professor Stratton, who is now the Director of the Wellcome Sanger Institute in Cambridge, UK. “But we decided to do something different.”
There was evidence that BRCA1 might not be the only gene linked to breast cancer. Could there be another? Stratton, who back then had only recently started leading his own group at The Institute of Cancer Research (ICR), turned his focus to the hunt for a second gene. It was a risky strategy.
“Whether there was one or not, was not at all clear at that time. Indeed, there were those who felt strongly that there was only one of these high-risk genes and that BRCA1 was it. Nevertheless, we felt that if there was a second gene like it, that would be an important thing to follow through.”
With funding from one of our forerunners – Cancer Research Campaign – the Medical Research Council and others, Stratton’s team began searching. The first thing they needed was a collection of families who were strongly affected by breast cancer, which led them to Ireland.
“We wrote to all the oncologists and one replied, Peter Daly. He was working with a family in Ireland who had 4 cases of breast cancer, 4 sisters who were diagnosed at a young age. By the time we started working with him that had become 5 sisters. And our first job was to find out whether this cluster was due to BRCA1.”
Early on, the team got a signal that it wasn’t, which gave them strong evidence that another gene existed.
Armed with this knowledge, the team followed a similar process that led to the localisation of BRCA1, scouring the human genome for stretches of DNA that everyone in the family who had breast cancer had in common. But after 7 months, they hit a wall. “We really couldn’t find it. It was one of those moments when your team looks to you for inspiration or new ideas, and the best I could come up with was: let’s do it all again. So we did.”
The team’s persistence paid off. Stratton says he remembers the afternoon that one of his team, Richard Wooster, came into the office with an x-ray film that appeared to show the location of the elusive second gene, on one of the 23 different chromosomes that makes up the human genome. “We came into work that morning not knowing where the gene was, and we went home that evening knowing it was on chromosome 13.”
The next step was to precisely identify which gene on this massive stretch of DNA was responsible – something that, back before the publication of the full map of the human genome, was a painstaking task. And it quickly became a race, as former collaborators in the US teamed up with a genetics company who wanted to find and patent the gene, something that Stratton was strongly against.
Teaming up with labs across the world, including that of his colleague Professor Alan Ashworth at the ICR and scientists at the Wellcome Sanger Institute, they began the laborious process of identifying which gene on chromosome 13 was BRCA2.
“It seems amazing looking back that we had to physically find genes, rather than just looking them up,” says Ashworth. “But the human genome wasn’t available at that time.”
After homing in on a section of DNA with abnormalities, the team worked tirelessly unscramble the mess and check if similar faults were also found in other samples in the same region. It was painstaking work, but it paid off. They had found BRCA2.
“It was a real rollercoaster, the intensity of work by the team that went into that final phase was absolutely extraordinary,” says Stratton. “And it was an amazing collaboration with other groups and the support of so many families who had been affected by breast cancer.”
The team published their findings in the journal Nature in December 1995, 25 years ago.
The discovery had an almost immediate impact. “We had a lady whose family had many cases of breast cancer. We didn’t know at the time whether those cancers were caused by BRCA mutations, but what we did know through working with her was that she did not want to get breast cancer.” With a young family to keep in mind, the woman was considering having preventative surgery to remove her breasts.
“But when we discovered BRCA2, it was possible to sequence her DNA and the DNA of members of her family to identify what was responsible. It turned out that other family members carried BRCA2 mutations, but she didn’t. So she was saved from having that surgery.”
BRCA mutations and cancer risk
Carrying a fault version of a BRCA gene means a woman has around a 70% chance of developing breast cancer by the age of 80, compared with around a 12% chance in the general population – though this does vary with other breast cancer risk factors.
BRCA2 mutations are also linked to prostate cancer, with one cohort study showing that prostate cancer risk is up to 5 times higher in men with BRCA2 mutation compared with the general population.
Since then, Stratton estimates that hundreds of thousands, if not millions, of people have been tested for BRCA1 and BRCA2 faults, giving them more certainty about their future, as well as options to reduce their risk, including surgery or preventative drugs.
The discovery of BRCA genes also paved the way for research that’s identified more subtle DNA variations that could impact someone’s risk of cancer. This knowledge is now being tested in the clinic, with our scientists creating the most comprehensive method yet to predict a woman’s risk of breast cancer in 2019, taking into account more than 300 genetic indicators.
Developing new treatments
But the story doesn’t stop there. Following the discovery of BRCA2, Ashworth and others worked to understand what it actually did and how it was linked to cancer. “We uncovered a particular function of BRCA2 in a DNA repair pathway,” says Ashworth. This kicked in when both strands of the DNA double-helix ‘ladder’ are broken – a situation that can be catastrophic for a cell. “And that gave us an insight into how to treat BRCA-mutated cancers.”
Both BRCA1 and BRCA2 instruct cells to make proteins that help repair damage to their DNA – something that occurs constantly over a cell’s life. But if a cell picks up damage to either BRCA gene, then its ability to repair its DNA is impaired, increasing the chances of the cell becoming cancerous.
But there’s a catch. As cells can only tolerate so much damage before they die, BRCA faults also push them closer to the edge – a discovery that Ashworth was keen to exploit.
With BRCA-mutant cells’ DNA repair systems already impaired, Ashworth’s team believed that impairing it further might tip cells over the cell, killing them. And they were right. In 2005, scientists showed that cancer cells bearing BRCA faults were exquisitely vulnerable to experimental cancer drugs known as PARP inhibitors, which are designed to hobble a completely separate part of a cell’s DNA repair system.
It’s a discovery that oncologist Professor Ruth Plummer remembers well. Plummer was already the first person in the world to have written a prescription for a PARP inhibitor, with the first PARP inhibitor developed by the Newcastle Drug Discovery team and funded by Cancer Research UK. This drug, now licensed as rucaparib, was already in trials in combination with chemotherapy. But the potential of PARP inhibitors in BRCA cancers excited Plummer further.
“I saw the data from the Newcastle group before it was published and within 6 weeks we’d applied to Cancer Research UK to do the first ever BRCA-focused clinical trial with a PARP inhibitor.
“It was really exciting because although at that point we still hadn’t got the dosing right, or worked everything out, the second patient we ever trialled this on responded. So we got a signal really early on that the scientists could be right.”
There are a now a number of PARP inhibitors – including olaparib and rucaparib – licensed for people with BRCA-related ovarian, breast, fallopian tube, pancreatic and prostate cancers. Over 30,000 patients have been treated with olaparib so far and that number is growing rapidly.
It’s also becoming increasingly clear that PARP inhibitors like olaparib and rucaparib are effective in treating a wider group of patients with DNA repair defects, with trials ongoing. And researchers aren’t stopping there. As well as developing new and better ways to predict who could respond to PARP inhibitors, Plummer is also involved in trials testing whether combining a PARP inhibitor with immunotherapy treatments is beneficial.
“It’s so much better to have this knowledge”
“The discovery of BRCA2 has had a huge impact on my life, and that of my children and my family. Finding out that I had the gene was obviously hard to process, and it was difficult to think about the future of my family, but it is so much better to have this knowledge.”
Mum-of-two Natalie Hall, 45, from Marlow, was diagnosed with breast cancer in 2019. She did not discover until months after diagnosis that there had been cancer on her father’s side too. She subsequently tested positive for the BRCA2 gene.
“For me, it meant that I had a preventative double mastectomy and an oopherectomy after my original breast cancer treatment.” The discovery that Natalie had a BRCA2 fault also meant that her cancer could be targeted with an extra chemotherapy that was thought to be more effective.
“The knowledge about BRCA2 has potentially given me my life and more options for my children too. I would like to thank the scientists for their work, and to highlight all the research that has happened as a result of that discovery to improve treatments.”
A different world
25 years on, it’s a completely different world for scientists like Ashworth and Stratton, both in terms of the information that’s available to us and the technology to exploit it, largely due to the work of the Human Genome Project.
It’s strange to look back for Ashworth. “On one hand, it feels like yesterday, on the other hand, it feels like a different age.” And while the scientists didn’t get to celebrate the occasion in person, the work will always mean a lot to those who were there. “To this day, when I meet someone who has been treated with a PARP inhibitor, it gives me a shiver to think I played a part in its development.”
But while the technology has moved on dramatically, Stratton’s approach to research remains unchanged. “Asking those big, high-risk questions brings many joys and potentially much success. You’re continually aware that you might fail in the race, or the thing you’re chasing after might not exist, but if it does the impact will be huge. So, that’s always the way we have operated.”
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