Scientists will have to rethink how environmental triggers allow tumours to form and develop, one of Britain’s leading cancer experts warned last week. Michael Stratton, director of the Wellcome Sanger Institute, said recent results from an international cancer research study – which aimed to pinpoint environmental triggers involved in oeosophageal cancer – indicated current scientific understanding of tumour formation was inadequate.
The research – on a type known as oesophageal squamous cell carcinoma – was aimed at uncovering why certain parts of the world suffer extremely high rates of the disease. These areas include parts of Iran, Turkey, Kenya and China where the disease is the most common form of cancer. In many other parts of the world, its incidence is relatively low.
“All sorts of different external factors have been put forward to explain these high rates,” said Stratton. “Some researchers have suggested there is a link with high levels of alcohol consumption, for example. But Iran has very low levels of drinking. Others have suggested that oil fumes from cooking could be involved. However, there seems to be no common denominator between these different regions that can explain these high rates. It has been a real puzzle.”
To try to solve the mystery, Stratton and his team were awarded £20m by Cancer Grand Challenges – an initiative founded by Cancer Research UK and the National Cancer Institute in the US. With this backing, his group is now studying the genomes of several types of tumour, with work beginning on oesophageal squamous carcinoma.
Oesophageal cancer can be difficult to treat because it is frequently diagnosed a long time after a tumour has started to form inside a person’s throat. “There is a particularly high incidence in Kenya and given the general stigma associated with cancer there, many patients do not go straight to doctors or hospitals and instead go to faith healers or herbalists,” said Mimi McCord, who has been involved in the study as a patients’ advocate.
“Their symptoms deteriorate and relatives end up bringing them to central hospitals from all over the country. By then it is usually too late for most of them.”
To pinpoint the environmental triggers that might be involved in these cases and in other oesophageal cancer hot spots, scientists began taking tumour tissue and blood from affected people. “We took samples from several hundred people from Kenya, Iran and other areas,” said Paul Brennan, from the International Agency for Research on Cancer in Lyon, France, which was also involved in the project. “Each person supplied a sample of their tumour and of their blood.”
With this material, researchers then began searching for “a mutational signature” in the tumour’s genome. “A mutational signature is a particular pattern of mutations in the DNA of some cancers – for example lung and skin cancers. In the case of lung cancer, it is caused by tobacco, and in the case of skin cancer, it is triggered by the ultra-violet component of sunlight,” Stratton told the Observer.
“You can often look at a cancer genome and, from the mutational signatures that are present, you get a pretty good idea of what caused that cancer.”
The aim of the CRUK study was to uncover a similar mutational signature for oesophageal cancer, one that would point to the environmental cause for the disease’s high rates in Kenya and other nations. However, to their considerable surprise, the scientists were unable to pinpoint any signatures that indicated a chemical or other factor had triggered the mutations that cause an oesophageal cell to become cancerous.
“It is a setback, because if we had found a distinctive mutational signature, we would have been able to make hypotheses about its cause – something in the diets or habits of groups with high oesophageal cancer rates,” said Stratton. “We would then have been on track to identifying the cause and find public health solutions to the problem. Sadly we still cannot do that.”
The study, published last week in Nature Genetics, indicates that scientists will have to think more broadly about the factors that cause cancer, Stratton added.
“Yes, external factors can trigger oesophageal squamous carcinoma – but not by directly causing mutations. In other words, we have found evidence that chemicals might be able to work in different ways other than directly causing mutations to increase a person’s chances of developing cancer. That is the message we need to take from this study – which has been backed by experiments on animals. We will have to rethink our ideas about the way in which some cancers develop. It is a crucial lesson.”