Chasing down the APC bowel cancer gene

In this next post in Our Milestone series, we take a look at how our scientists in the late 80s laid the foundations for the discovery of an important bowel cancer gene called APC  – now known to be faulty in around eight out of ten cases of the disease.Publishing their research in two back-to-back papers in the journal Nature (here and here), the scientists – led by Professors Walter Bodmer and Ellen Solomon – tracked down the location of APC, paving the way for its eventual identification in 1991.

Thanks to the discovery, members of unfortunate families in which many cases of bowel cancer occur – often at a young age – can now be offered life-saving genetic tests and screening.

Studying APC and related genes has also led scientists to uncover the role of other important molecules that are involved in several types of cancer. This painstaking research is helping us to understand how cancer develops at a molecular level, laying the foundations for the development of future treatments.

Let’s look in a bit more detail at this landmark discovery, and what it means for bowel cancer patients and their families.

A bit of background

Professor Walter Bodmer, along with his colleague Professor Ellen Solomon, helped to locate the APC gene in the 1980s

Cancer Research UK’s involvement in bowel cancer research stretches back nearly a century, starting with funding the pioneering researchers John Percy Lockhart-Mummery and Cuthbert Dukes at St Mark’s Hospital in London.

Most cases of bowel cancer occur in people with no obvious family history. But sometimes whole families are affected, with many family members developing the disease, particularly at a young age.

As far back as 1925, Lockhart-Mummery noticed that people in some of these families suffered from a condition called familial adenomatous polyposis, or FAP, which causes hundreds of tiny pre-cancerous lumps (polyps) in the bowel.  Over time, one or more of these lumps can develop into a tumour, meaning that a person with FAP will almost inevitably develop bowel cancer by their 40^th birthday.

Importantly, Lockhart-Mummery realised that the condition must be caused by a “dominant” inherited gene fault, meaning that a person only has to inherit a single faulty copy of the gene from one of their parents, rather than two (one from each parent) in order to have FAP.

Sadly for families affected by FAP, it wasn’t until the technological advances of the 1980s that it became possible to identify the faulty gene that lay at the heart of their condition.  And a big part of that was down to the diligent work of the Cancer Research UK team.

Tracking down APC

Buoyed by the growing interest in cancer genes in the 80s, the Imperial Cancer Research Fund (ICRF – Cancer Research UK’s predecessor) decided to strengthen its research in genetics. To help achieve this they appointed Professor Bodmer – a highly respected genetics expert – as Director of the ICRF Laboratories in 1979.

As a geneticist running a major cancer research institute, Professor Bodmer was keen to get his teeth into studying cancer genes, and had FAP in his sights. He was also aware that St Mark’s had built up an impressive resource of families affected by FAP, along with DNA analysis techniques that were just starting to become available.

Putting the two together – with the help of his late wife Julia – Professor Bodmer forged a close collaboration with the researchers at St Mark’s, and got to work.

The first hint as to the location of the gene that caused FAP came from a paper published in 1986 by a US team, describing a man with FAP who was found to have a region missing from one of his two copies of chromosome 5 (humans have 23 pairs of chromosomes in each of their cells, which carry their DNA).

Although this was a step in the right direction, it was a long way from finding and identifying the gene responsible for the syndrome. To use an analogy, it was like being told that there was a typo in a particular chapter of a book – but not what the typo was, what sentence it was in, or what it ‘meant’.

First catch your families

To find the gene itself, Professor Bodmer and his team used a detailed registry of families with bowel cancer, collected over the years by doctors at St Mark’s in London and Broadgreen Hospital in Liverpool.

Using the information in this registry, Professor Bodmer’s team collected blood samples from many members of the families, including people with FAP and their unaffected relations, to provide DNA.

The researchers also created ‘immortalised’ cells from these blood samples – cells that would keep on growing in the lab indefinitely – so they would always have a source of DNA to study, without having to go back for more blood samples from the families.

Then, using a variety of lab techniques including gel electrophoresis and Southern blotting, they were able to analyse these samples for regions of DNA that were present only in people who had FAP.

Zooming in

Professor Bodmer’s team set to work testing DNA from 124 members of 13 affected families – a painstaking and laborious task using the technology of the time. But the results were worth it.

When they checked which regions of DNA were altered in family members with FAP but not in their unaffected relatives, one region of chromosome 5 always stood out in the DNA of family members with FAP, in all the families. And – excitingly – this was exactly the same region of chromosome 5 that the US team had identified in 1986, strongly indicating that it contained the gene that caused FAP.

As Professor Bodmer’s team was focusing on FAP families, elsewhere at the ICRF labs Professor Ellen Solomon and her team – who were working closely with Professor Bodmer in the hunt for the gene behind FAP – found another crucial piece of the puzzle.

Proving the link

Professor Solomon and her team were following up on a suggestion first put forward in 1971 – that faults in genes causing inherited cancers may also be involved in non-hereditary, randomly-occurring (sporadic) cancers too.

The researchers studied samples of bowel tumours and healthy bowel tissue taken from 45 patients, most of them treated for cancer at St Mark’s.  Unlike the FAP families studied in Professor Bodmer’s lab, all of these cancers had arisen randomly in people with no family history of the disease.

Using a similar technique to Bodmer’s lab, Solomon and her team compared DNA from each patient’s tumour with DNA from their healthy bowel tissue. In this case, they were looking for differences between chromosome 5 in healthy and cancerous tissue, which would suggest that a genetic change occurring during a person’s lifetime had contributed to the development of their cancer.

The researchers noticed that the same region of DNA on chromosome 5 Bodmer’s team were homing in on, was missing in just under a quarter of all the tumour samples they tested, yet it was there in DNA from healthy tissue from the same patients. And when they looked more closely, nearly 40 per cent of cancer samples (including bowel cancer cell lines grown in the lab) showed at least some sign of a fault in that particular part of chromosome 5.

But was this just a random genetic mistake in the tumours? After all, the chromosomes in cancer cells are pretty messed up.

To confirm that the fault on chromosome 5 was causing bowel cancer, the researchers looked at other chromosomes, including regions known to harbour genes involved in other cancers.

Reassuringly, there was no noticeable pattern of faults in these regions, strongly suggesting that a fault on chromosome 5 was the main genetic mistake in the bowel tumour samples. Such a result – finding a single fault in lots of different samples – is tantamount to a smoking gun when looking for cancer genes.

Pipped to the post

Added together, the results from both teams confirmed that the gene that causes FAP – and probably a significant proportion of sporadic bowel cancers – was located in a very small region of chromosome 5. Although this is a relatively precise area in genetic terms, it still contained an unknown number of genes – any one of which could have been the culprit causing FAP.

By publishing their papers in Nature, Professors Bodmer and Solomon showed the world they were tantalisingly close to tracking down the gene. But although they didn’t have the FAP gene’s exact ‘address’, they had told everyone the equivalent of the genetic ‘street’ it lived on.

The race was now on to find the gene itself, and although our scientists worked as fast as they could, they were pipped to the post in 1991 by two research groups in the US – one from Utah and the other in Baltimore – who homed in on the precise gene responsible for FAP.

This wouldn’t have been possible without our researchers’ vital ‘map’ that led others to the treasure.  And our scientists were the first to show that the same gene was likely to be involved in both sporadic and hereditary cancers.

Lifesaving knowledge

Thanks to the efforts of all the researchers involved, the gene responsible for FAP – now named APC, short for adenomatous polyposis coli – now had an identity.  Scientists around the world immediately set to work trying to figure out how this could be used to benefit cancer patients and their families.

Finding APC meant that people from families affected by multiple cases of bowel cancer could be offered a genetic test, identifying those with a faulty version of the gene who are at high risk of developing the disease. As a result, regular bowel screening is now available for people with FAP from a young age, although they are also strongly advised to have their bowel removed as a preventive measure.

Thanks to the discovery that APC is implicated in sporadic cancers, the impact of the gene’s identification has spread much further than the relatively small number of families affected by FAP.

We now know that APC is a ‘tumour suppressor’ – a gene that normally protects us from cancer by preventing cells from multiplying out of control.

Faults in the gene are found in around 8 out of ten bowel cancers, both hereditary and sporadic. These mistakes stop APC from working properly, increasing the chances that cells will multiply unchecked and ultimately lead to cancer.

Even though it was discovered two decades ago, APC still presents a challenge to bowel cancer researchers.  For a start, it appears to be an adept molecular ‘multitasker’, carrying out several jobs at once in cells, including controlling how fast cells multiply, how they stick to their neighbours, and how they move.

Much of this groundbreaking work was carried out by Cancer Research UK-funded scientists. For example, our scientists in Dundee discovered that APC helps bowel cells to know which way is ‘up’. And a team at the Cancer Research UK Beatson Research Institute in Glasgow discovered that a loss of APC in bowel stem cells fuels the growth of tumours.

Although we’re yet to see the benefits of this research filter all the way through to treatments for bowel cancer patients, our growing understanding about how APC works – and what happens when it doesn’t – is paving the way for powerful ways to target the disease in the future.

From one gene to many

Since the discovery of APC, our scientists have continued to make important contributions to our understanding of the genes involved in bowel cancer, publishing hundreds of papers in the process.

For example, we helped to fund research identifying the first common bowel cancer gene and a rare new gene, as well as variations in certain genes that can together triple bowel cancer risk. And in 2010, our researchers discovered four completely new gene variations that can increase a person’s risk of the disease.

We’re making steady progress in understanding how variations in our genes interact with our lifestyle and environment to influence our individual chances of developing bowel cancer.  It’s only a matter of time before we start to see more personalised predictions of bowel cancer risk, along with tailored prevention measures that will help to cut deaths from the disease.

And although we’ve come a long way from the days of the painstaking experiments carried out by Professor Bodmer and his colleagues – now that a person or tumour’s entire genome can be read in a matter of days – their work provided the foundations on which this is built.

Finally, it’s important to recognise the contribution of the doctors at St Mark’s and other cancer hospitals, without whose carefully compiled registries and sample collections this research simply wouldn’t have been possible.

But the biggest debt of thanks belongs to the cancer patients and their families who agreed to be involved in the studies. Although the benefits of APC’s discovery may have come too late to help many patients personally, being part of the project doubtless helped to reveal more about cancer risk within their own families.  Their contribution has already saved lives and will continue to do so in years to come.

Kat

References:
Solomon E, et al. (1987). Chromosome 5 allele loss in human colorectal carcinomas. Nature, 328 (6131), 616-9 PMID: 2886919

Bodmer WF, et al. (1987). Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature, 328 (6131), 614-6 PMID: 3039373