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Bowel cancer cells

Our researchers have found a new sub-type of bowel cancer

Thanks to advances in research over the years, we know more about cancer than ever before, with new discoveries being made all the time. In some cases this knowledge has led to life-saving new treatments. In others, it causes frustration and head-scratching until more pieces of the puzzle fall into place.

For example, why do some patients with the same type of cancer respond to a treatment but others don’t? And what makes some cancers grow and spread aggressively while others are less dangerous?

Thanks to research, answers to these questions are coming. Much of this progress hinges on the use of new technology to analyse the faulty genes in cancer cells, enabling researchers and doctors to characterise the molecular fingerprint of an individual person’s cancer and select the most appropriate treatment.

As an example, last year our scientists showed that, based on the genetic makeup of each patient’s  disease, breast cancer can be divided into at least ten distinct subtypes, each with different outlooks and responses to treatment.

Now it’s bowel cancer’s turn under the spotlight, as researchers at our Cambridge Institute – along with colleagues in the Netherlands and Oxford – have discovered a new subtype of bowel cancer, which has a worse outcome than other types and is resistant to current targeted treatments.

Published in the journal Nature Medicine, their results have big implications for patients and future research.

Deciphering the signature

The researchers analysed the activity patterns of thousands of genes in tumour samples from 90 patients with what’s known as ‘stage II’ bowel cancer – where the cancer has just started spreading out of the bowel into the surrounding organs. They found that the patterns fell into three broad groups, which they call CCS1 (for Colon Cancer Subtype 1), CCS2 and CCS3. We’ll refer to them here just as Group 1, 2 and 3 to keep it simple.

The scientists then narrowed down a set of just 146 genes that could accurately distinguish between the three types – essentially a molecular fingerprint for each type of the disease.

Using this, they worked out that nearly half of the patients had Group 1 tumours, while roughly a quarter were affected with Group 2 and a quarter with Group 3. The team confirmed their findings by looking at the patterns of gene activity in tumour samples from a larger group of just over 1,000 bowel cancer patients.

So far, so interesting. But what do these different subtypes actually mean?

It turns out that the tumours in Group 1 and 2 are already familiar to bowel cancer researchers. Group 1 cancers are known as “chromosomal instable” tumours, which we recently wrote about, that have a lot of broken and messed-up chromosomes. By contrast, Group 2 tumours are called “microsatellite instable” and have changes in the lengths of short repeated sequences of DNA known as microsatellites – it’s a kind of genetic ‘fuzziness’.

The newly discovered Group 3 tumours are different. They don’t have chromosome or microsatellite instability, and they’re more likely to have faults in specific genes (such as BRAF and KRAS) than the other types.

When the researchers compared how long each group of patients had survived, people with Group 3 cancers generally had a worse outlook. Many had more aggressive tumours that grew and spread faster than those in the other groups. And in more than half of all cases, the cancer came back within two years.

And there’s more. The scientists found that the Group 3 tumours were much more likely to be resistant to treatment with cetuximab (Erbitux) – a commonly-used drug targeted against a molecule called EGFR (which our scientists helped to discover) on the surface of bowel cancer cells.

Putting it all together, this is a hugely important discovery. Not only have the researchers revealed a whole new subtype of bowel cancer that was previously elusive, it also looks like these tumours are more aggressive, harder to treat and have poorer survival than other types.

On the surface this sounds like bad news, but, as we’ll see below, it opens the door to much more effective approaches for identifying and treating patients with these types of tumour in the future.

Going back to the roots

There’s one more important question that the researchers needed to answer – where do these Group 3 tumours come from?

To find out, they compared the genetic fingerprints of different types of precancerous bowel lumps (lesions) to the signatures of the different subtypes of bowel cancer. They discovered that Group 3 cancers shared their genetic makeup with lesions known as serrated adenomas, which develop in a different way from the precursors of Group 1 or 2 tumours.

The researchers also found that genes linked to aggressive growth and cancer spread were more active in Group 3 tumours. And they spotted rogue activity patterns of genes that switch cells from being a well-behaved part of the lining of the bowel to becoming ‘free agents’ that can invade nearby tissues.

Significantly, they noticed that many of these genes are already active in precancerous serrated adenomas, suggesting that they’re somehow primed to spread from an early stage – something that usually happens much later for other subtypes of bowel cancer. The researchers think that this may be due to the particular type of cell in the bowel that these Group 3 tumours start from, but more work needs to be done to figure out exactly what’s going on.

Again, this finding is highly significant as it tells us that there’s a group of patients whose tumours have the capacity for aggressive growth ‘hardwired’ into them practically from the start. The major challenge now is to work out which patients have these tumours, and find ways to treat them more effectively.

Where now?

There’s still a way to go before this knowledge can be applied to bowel cancer patients on a widespread basis, but there are some clear ways forward.

For a start, the team’s findings need to be confirmed in a larger number of patients, to make sure they hold up. Another important step will be to develop a reliable test that can identify which patients fall into which groups – something that should be possible in the not-too-distant future.

As part of this research, the team showed that an FDA-approved gene test called Oncotype DX, which looks at the activity levels of 21 genes and costs thousands of dollars, could distinguish patients with Group 3 tumours. But this test, and others like it, are designed to help doctors predict whether individual patients are likely to have a good or poor outlook (prognosis), not identify the specific gene faults that underpin their cancer (which would be important for selecting the most appropriate treatment).  

To solve this problem, the team developed a ‘mini-classifier’ panel of just four genes that could accurately distinguish between the different bowel cancer subtypes at a biological level, rather than just giving a “good or bad” read-out. Developing this kind of approach into a simple, cheap test that can be validated in a large number of patients could help doctors identify patients with more aggressive Group 3 cancers and help guide treatment decisions.

This research also has big implications for research into bowel cancer, as it turns out that current lab models of the disease are based on Group 1 and 2 tumours. Group 3 cancers are relatively unexplored territory, scientifically speaking, so much more work needs to be done to understand where they come from and how best to treat them.

By understanding the faulty genes and molecular pathways in these cancers, researchers will be able to develop more effective therapies specifically targeted at these aggressive tumours, which could save many lives in the future. One particularly exciting avenue is the TGF-beta pathway (which we’ve talked about before), which seems to be hyperactive in Group 3 tumours, so drugs that block TGF-beta (which are already in development) or related molecules might be useful, but this still needs to be investigated.

April is bowel cancer awareness month, and although we can’t control when our researchers publish their scientific papers, this new discovery is a timely reminder that research is the best weapon we have for beating this disease that claims more than 15,000 lives in the UK every year. And, one day, we will get there.

 Kat

Reference:         

De Sousa E Melo F. et al (2013). Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions, Nature Medicine, DOI:

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Comments

Kat Arney May 22, 2013

Hi Barbara,
Thanks for your comment, and we’re sorry to hear about what you’re going through. If you have any questions about cancer or your treatment, please give our Information Nurses a ring – they’re on Freephone 0808 800 4040 (9am-5pm Monday to Friday).
Best wishes,
Kat

Barbara Michael May 18, 2013

I am very interested in these findings and am wondering if I could have this agressive type of gene.I was diagnosed April 2010 stage Dukes B 2.After the operation end of AprilI was told 9 lymph nodes all clear either side of resection clear and to go home and get on with my life.6 months later my bloods went from 4 to 5.I had scans but they showed all clear..I continued with bowel cancer symptoms on and off diahorreah tiredness.for 2 years.Then 2012 april I had blood once more in stools.I had colonoscopy more scans with contrast but everything looked O.K.My blood levels went up to 19.I had colonoscopies 3 times over the 2 years and more scans than I should have.September 2012 I had 3 types of scans bloods had reached 29.Still nothing but was feeling very tired and unwell by then and looked yellow.In January 2013 a tumour was discoverd on my liver 1cm sizeafter a c.t scan and by then my cea blood levels were off the wall.I had to wait 3 months for a liver resection and by then the tumour had grown so large I had 72 per cent liver removed.So you see from being told to get on with my life so much has happened to me in a short space of time I am 70 years of age This is why I am interested in your new findings

Ruth May 4, 2013

I had cancer of the rectum in may 2011 so its now 2 years on and Im having 6 monthly checks for 5 years and then hopefuly the all clear. I feel a bit worried like Dorothy but hope that I will be lucky like Karen. I lead a normal life at the moment and long may that continue. My doctor spotted my symptoms very early so I was only stage 1 and my surgeon removed all of the tumour so I am eternally grateful to him Cancer Research and my doctor. Keep up the good work :)

Karen Sanderson May 3, 2013

Dorothy Byres, having had colon cancer myself. I went for a Colonoscopy every 3 year’s . After the 5 yr mark, I would be screen every 5 yrs. If you are concerned about your screening, I would think it best to speak to your G.P, or specialist. I hope you keep well :)

Karen Sanderson May 3, 2013

Its great new’s to hear that so much research is now taking place, and ways to treat different types and stages of bowel cancer.

I had bowel cancer when I was 29yrs old. Thanks to an excellent surgeon and his team, also to the Oncologist, I am here to see my children grow up. I am 17yrs Cancer free. Without cancer research, so many people would not be here to tell their story.

Dorothy Byres May 3, 2013

Always delighted to hear of all the progress being made with research. Despite having a good diet and lifestyle I had stage 3 bowel cancer, two years ago aged 52. I now have check-ups very 6 moths and am concerned that when they drop to annually they will not be frequent enough. I hear so many stories of people going for a check-up and discovering an aggressive return. In an ideal world how often should people be reviewed?

susan hore May 2, 2013

i wsa diagnosed with stage 2 bowel cancer 10yrs ago which returned in my scar 5yrs later -i am fit and well again thanks to amazing surgeons and the fantastic work of cancer research —–thank you so much, without you i would not be here .

Eileen Slack May 2, 2013

Very interesting article.My mum died of bowel cancer many years ago.I had bowel cancer twenty years ago aged 45 I am fit and well Thank God .

Oliver Childs April 16, 2013

Dear Heather,

We are very sorry to hear about your dad. We wanted to let you know about Cancer Chat, an online forum for people affected by cancer. You may find some comfort in talking to others who have shared similar experiences. And our Cancer Information Nurses can point you in the right direction of further support. They can be called freephone 0808 800 4040.

Best wishes,
Oliver Childs
Cancer Research UK

John April 16, 2013

Very good article. So many people are fighting this disease and we need to give them all the information and support they need. We will find a cure

Heather Hughes April 14, 2013

please find a cure soon i lost my dad to a rare cancer 12th aug 2012 and it was a reall shock because up until that time he never had a days illness

Carol Baldwin April 14, 2013

Extremly informative. Good to read that progress is coming along in leaps and bounds giving those diagnosed more of a fighting chance! Keep up the good work!