Tracking down the BRCA1 gene

In this two-part post in Our Milestones series we look at our role in the discovery of two of the most famous “cancer genes” known to science – BRCA1 and BRCA2.

Faults in BRCA1 and BRA2 are responsible for most cases of hereditary breast cancer (around 5% of all breast cancers), as well as inherited ovarian and prostate cancers, and possibly more.

Thanks to the discovery of these genes, women at high risk of breast and ovarian cancer can now be offered genetic testing, along with lifesaving advice about prevention and screening for these diseases. And our scientists have been there all the way.

On your marks…

The starting line for the hunt for BRCA1 and BRCA2 was drawn back in the 1940s, before we fully understood how genes and DNA work.

British researcher Sir David Smithers, from the Royal Free Cancer Hospital, published a paper looking at the family trees of more than 450 breast cancer patients. He showed that breast cancer could occasionally run in families, with several relatives being affected by the disease across the generations.

Over the next few decades, as our picture of how genes work grew clearer, it became obvious that these hereditary cases of breast cancer were caused by a faulty gene or genes.

By the 1980s, as the genes involved in cancer were gradually revealed, this conundrum of inherited breast cancer was thrown into sharper focus.  What were these genes, and what did they do?

Get set…

In today’s era of high-speed technology, it’s possible to read an entire human genome in just a few days. But even just two decades ago, the picture was very different.

Identifying and locating genes took years of painstaking work at a pace that now seems unimaginably slow. Yet at the same time there was fierce competition around the world to be the first to identify the genetic culprits involved in particular diseases, and breast cancer was no exception.

By the late 1980s, researchers were scouring the human genome, searching for a gene dubbed “Breast Cancer 1”.  They were using the most sophisticated technique available at the time, known as linkage analysis, to home in on the region of the genome harbouring the gene.

Although this technique is relatively crude compared to today’s technology – it’s the equivalent of narrowing down the search for a missing person from the whole of the UK to a major city – it was a major step forward in the hunt.

In the early 1990s, several research groups published papers showing that a region in the middle of human chromosome 17 was the likely location for Breast Cancer 1 (for example, here and here). Although this was significant progress, this region was still relatively big and potentially contained hundreds of genes – any one of which could have been the elusive breast cancer gene.

Cancer Research UK’s Professor Doug Easton is one of the researchers who helped to track down BRCA1

A major breakthrough came when a Cancer Research UK team (then The Cancer Research Campaign) led by Professor Doug Easton pulled together the results from all the linkage studies around the world. In a paper published in 1993, they analysed the combined data from more than 200 families affected by breast and ovarian cancer.

Their results narrowed down the search to a smaller region of chromosome 17, and showed that a faulty gene in this region accounted for most of the families affected by many cases of breast and ovarian cancer. But it also confirmed that there must be other breast cancer genes lurking elsewhere – a story we’ll return to in part 2.

Now that Professor Easton’s team had confirmed that that the region on chromosome 17 definitely harboured a breast and ovarian cancer gene – and it had been reduced to a much more manageable size – the BRCA1 race was on.

Go!

First out of the blocks was a team including The Cancer Research Campaign’s Cambridge-based Human Cancer Genetics Research Group led by Professor Bruce Ponder (who went on to become the first director of the Cancer Research UK Cambridge Research Institute). In May 1994 they published a paper narrowing down the possible BRCA1-containing region even further.

In August that year, Ponder‘s team – together with colleagues in the US – published a paper in the journal Nature Genetics detailing a ‘map’ of the region on chromosome 17, pinpointing more than 20 genes within it that were possible candidates for BRCA1. Not only was this a paper map, the scientists had also built a physical ‘map’ made up of small pieces of DNA spanning the region, cleverly smuggled into yeast and bacterial cells so they could be studied in the lab.

This map laid out the racecourse. All that was needed now was to ‘read’ the sequences of these DNA fragments, piece them together into whole genes, and then work out which gene had the same faults as those seen in women with hereditary breast cancer.

Though it sounds simple, it was a massive task. A number of research groups around the world threw their efforts into the race, all angling for the prize of finding the first breast cancer gene.

Announcing the winners

Throughout 1994, various teams published papers describing how they were inching ever closer to the prize, but by October the race was over.

First across the line was a team of US scientists led by Professor Mark Skolnick. Writing in the journal Science, the team revealed the identity of the gene now known as BRCA1, proving that it was faulty in a number of families affected by hereditary breast and ovarian cancer.

Although reports at the time talked about “winners” and “losers” in the race to track down the gene, the ultimate winners are cancer patients and their families. From genetic testing to targeted treatments, we’ll take a look at the benefits of finding the BRCA genes in part 2 of this series.

It’s also important to remember that without the dedicated work of Cancer Research UK’s scientists, along with their colleagues around the world, the identity of BRCA1 would still remain a mystery.

But the scientific community couldn’t rest on their laurels. As we mentioned, Professor Easton’s work hinted that there must be other breast cancer genes out there. And a paper published in the same edition of Science as the unveiling of BRCA1 revealed that the gene was faulty in only a small proportion of cancers – 3 out of 32 breast cancers and 1 out of 12 ovarian cancers that had been studied.

The evidence suggested that there was at least one more important breast cancer gene still to be discovered. The hunt was now on for BRCA2.

• The story continues in part 2.

Kat