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Pieces falling into place: Genetic graffiti and PARP inhibitors

Research published today opens up the possibility that around 20% of breast cancer patients could benefit from drugs that have so far only been used in patients with inherited BRCA mutations. In this blog, we look at the many pieces of research that have contributed to this discovery.

Although the actual test and resulting “20%” figure in today’s research news has resulted from research from the last 4 years, it builds on work that stretches back to the ‘90s.

But before we do the time warp, let’s look at the most recent part of the puzzle by taking a short drive out of Cambridge to a village down the road…

Mapped out genes and genetic graffiti

Like most small English villages Hinxton has a pub, a church, a village hall… and a world leading genetics research centre – the Sanger Institute.

Teams of scientists based at the Sanger Institute, and their collaborators, including Breast Cancer Now scientist Prof Andrew Tutt, are focussed on understanding human genetics. Last year, we covered the news that they had mapped out possibly all of the genetic mutations that drive breast cancer: a feat achieved by reading all the 3 billion letters of DNA code in 560 breast cancer cases.

In separate work, the team had also documented over 20 'mutational signatures', or ‘genetic graffiti’ marks found in cancer’s DNA. They searched thousands of cancers and found that the majority had at least one of these genetic signatures. For example, over-exposure to UV light had left its mutational signature in melanoma (skin cancer), and the signature for smoking was found in lung cancer.

Interestingly for breast cancer, the researchers believed they’d also found more than one mutational signature linked to cancers caused by mutations in the BRCA1 or BRCA2 genes (and other breast cancer signatures we’ve reported on before).

But the reason they were interested in signatures from the BRCA genes takes us back to the ‘90s and to London…

BRCA gene mutations and PARP inhibitors

In the early 1990s a global research race was going on to find inherited genetic mutations that explained why some families had suffered breast and ovarian cancer throughout generations of women and men.

The man leading the effort at the Institute of Cancer Research (ICR) in London would later become director of the Sanger Institute (and be knighted), but that was a while off when Mike Stratton’s team at the ICR, with some support from Breast Cancer Now, made one of the key discoveries that linked mutations in the BRCA2 gene to breast cancer.

The next steps were not only to find women with this mutation and try to lower their risk of breast and ovarian cancer, but in women who did develop breast cancer to see if we could use this genetic knowledge to kill cancers caused by BRCA mutations.

To do this, scientists needed to understand why BRCA mutations were causing cancer in the first place. In all of our cells, we all carry copies of the BRCA genes, and they produce proteins which play key roles in repairing the day to day faults that build up in DNA, which they do via a process called homologous recombination (HR). But when the BRCA genes go wrong that repair process stops working, and not only does this cause cancer, but in order to survive those cancerous cells have to rely on other means to patch up their DNA.

As we’ve explored in more depth previously, it turns out that cancer cells end up relying on an enzyme called PARP to keep their DNA in shape. So when PARP is stopped or “inhibited” from doing its job, faults build up in cancer DNA that eventually cause cancer cells to self-destruct. This is the basic principle – known as ‘synthetic lethality’ - behind using PARP inhibitors in cancers with BRCA mutations – a principle that was uncovered by scientists at our Research Centre in 2005.

However, breast cancers caused by inherited BRCA mutations account for a small number, about 1-5%, of all breast cancer cases. So although PARP inhibitors have shown promise in clinical trials (and have been approved for use in ovarian cancer), doctors didn’t think they’d be useful for breast cancer patients without a BRCA mutation - until now.

BRCA’s signature graffiti

Drawing on all of this historic research, scientists at the Sanger Institute took a new approach to analysing the 560 breast cancer cases they had mapped the genetic mutations of. And that’s where today’s finding comes from.

In these 560 breast cancer cases, the researchers identified 77 people whose cancer was being driven to grow by a BRCA gene mutation. They then compared these cancers to those that were being driven to grow by completely different genetic errors.

By doing this they found six mutational signatures that looked identical to the ‘genetic graffiti’ left from having a faulty BRCA gene. This was found using a computer algorithm which they called ‘HRDetect’ because the mutational signatures actually indicate cancers whose homologous recombination (HR) process has gone wrong – as it does in cancers with BRCA mutations.

What was detected by HRDetect?

The Sanger scientists used HRDetect to analyse their 560 breast cancers and found 124 samples where there was a high chance of the cancer having a broken HR system. This included an additional 47 cancers to the 77 cancers with BRCA mutations that they had already found.

The interesting thing was, although these 47 cancers had a broken HR system, they didn’t actually have BRCA mutations.

Adding these 47 new samples to the 77 with BRCA mutations meant there were 124 cancers out of 560 cancers (22% or “around 20%”) that could potentially be killed with PARP inhibitors.

What’s next?

Along with the researchers behind today’s results, we think that HRDetect is a valuable tool that could now be used to identify breast cancer patients to take part in clinical trials of PARP inhibitors.

The scientists have also begun testing samples from ovarian and pancreatic cancers using HRDetect, to see if they can find patients with these cancers who might also benefit from PARP inhibitors.

Overall the results from today show that by building on past discoveries, research continues to find pioneering ways of understanding cancer on completely new levels, bringing us ever closer to a time where everyone who develops the disease lives.

More information

Read our comment on the study's findings


Image credit: - Wojtek Galaj


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