Genetic ‘switch’ enables bowel cancer cells to outrun the immune system

Bowel cancer cells can perform an “evolutionary balancing act” that allows them to adapt, giving them the best chance of developing and surviving, researchers in Europe have found.

The discovery of a genetic “switch” that allows the cancer cells to outwit the body’s immune system by regulating their growth could pave the way for more focused medicines, according to scientists at University College London and University Medical Center Utrecht who made the discovery.

Their study, published in published in Nature Genetics, looked at genetic mutations in cancer cells which were originally believed to occur as a matter of chance.

They found, however, that mutations in DNA repair genes could be repeatedly created and repaired, acting as “genetic switches” that “take the brakes off a tumour’s growth or put the brakes back on, depending on what would be most beneficial for the cancer to develop”.

A joint news release from UCL Cancer Institute and UMC Utrecht explained: “Cancer is a genetic disease caused by mutations in our DNA. DNA damage occurs throughout life, both naturally and due to environmental factors.

“To cope with this, cells have evolved strategies to protect the integrity of the genetic code, but if mutations accumulate in key genes linked to cancer, tumours can develop.”

According to the researchers, around one in five bowel cancers, known as mismatch repair deficient (dMMR) cancers, are caused by mutations in DNA repair genes. Disrupting these repair mechanisms, however, is not entirely beneficial to tumours. Though they do allow tumours to develop, each mutation increases the risk that the body’s immune system will be triggered to attack the tumour.

“Cancer cells need to acquire certain mutations to circumvent mechanisms that preserve our genetic code,” said Dr Marnix Jansen, senior author of the study. “But if a cancer cell acquires too many mutations, it is more likely to attract the attention of the immune system, because it’s so different from a normal cell.

“We predicted that understanding how tumours exploit faulty DNA repair to drive tumour growth – whilst simultaneously avoiding immune detection – might help explain why the immune system sometimes fails to control cancer development.”

Understanding how bowel cancer cells are able to regulate tumour growth could potentially be used in personalised cancer medicine, allowing doctors to determine how aggressive an individual’s cancer is so that they can configure the most effective treatment.

It could mean, for example, more intense treatment if DNA repair has been switched off and there is potential for the tumour to adapt more quickly to evade treatment – particularly to immunotherapies, which are designed to target heavily mutated tumours.

The researchers have already embarked on a follow-up study to find out what happens to these DNA repair switches in patients who receive cancer treatment.

Dr Hugo Snippert, a senior author of the study from University Medical Center Utrecht, said: “Overall our research shows that mutation rate is adaptable in tumours and facilitates their quest to obtain optimal evolutionary fitness. New drugs might look to disable this switch to drive effective immune recognition and, hopefully, produce better treatment outcomes for affected patients.”

Georgia Sturt, Research and Grants Manager at Bowel Research UK, said: “Cancer’s evasion of immune system destruction is a key element of its ability to grow and spread. Understanding exactly how bowel cancers do this is crucial to optimising treatment for patients.”

Australia has one of the highest rates of bowel cancer in the world, with 1-in-15 Australians developing the disease in their lifetime. It is Australia’s second deadliest cancer.