The genes in which mutations can lead to childhood cancer share a feature: they do not vary like other genes. In a sweeping new study, the evidence of evolutionary pressure is staggering. A researcher says that this new lens for understanding genetic risk of childhood cancer may have considerable clinical implications.
When children develop cancer, this often results from congenital mutations in various genes – unlike cancer among adults, which can be caused by smoking, alcohol, air pollution, unhealthy lifestyles and other factors.
Research has not focused much on the evolutionary genetic background for childhood cancer, but researchers have conducted a major study investigating the role of evolution in children’s risk of developing cancer.
The research shows how the genes associated with an increased risk of childhood cancer have been under substantial evolutionary pressure throughout human existence. This means that these genes vary little between people.
“This is a new way of investigating the associations between genes and childhood diseases. Evolution has a role because it determines whether some genes are more protected against mutations than others,” explains a researcher behind the study, Ulrik Kristoffer Stoltze, Paediatrics Oncology Research Laboratory, Rigshospitalet, Copenhagen, Denmark.
The research has been published in Nature Communications.
Mutations in 85 genes can lead to childhood cancer
Some children have a higher risk of developing cancer than others because specific genes have variants that promote the development of cancer.
A genetic predisposition for increased risk of developing cancer is likely to be deselected from an evolutionary perspective, and this genetic risk will disappear over time.
In other words, people with a high genetic risk of developing cancer in childhood are less likely to have children themselves, and their genes therefore die out.
A child’s risk of developing cancer is often linked to 85 specific genes that have mutations associated with increased risk.
Most other human genes can tolerate mutations better, and this inherently indicates their lack of typical associations with the development of childhood cancer.
“Over evolutionary time, several mutations may accumulate in some genes without harm to the carrier, whereas not having too many in other genes is preferable – especially genetic mutations that can lead to the development of childhood cancer,” says Ulrik Kristoffer Stoltze.
Cancer risk is like a bomber
Ulrik Kristoffer Stoltze compares children’s cancer risk with British bombers in the Second World War.
When the British bombers came back from raids over Germany, many of them had bullet holes in various places in the airframe.
In this situation, some aircraft mechanics suggested reinforcing the damaged areas of the bombers. However, others advocated reinforcing the areas with no bullet holes.
They argued that the undamaged areas were probably hit on the planes that never made it back to England and thus were probably the most vulnerable.
“This applies to the genes associated with children’s risk of cancer. Parts of the human gene pool have experienced many genetic changes over time, and others have not. The areas that do not experience genetic changes are those in which ‘bullet holes’ in the form of mutations have led to the children not surviving – including by developing childhood cancer. This provides insight into which genetic mutations are more harmful, because they can result in childhood cancer or other conditions that limit the probability of being able to pass on genes to the next generation,” explains Ulrik Kristoffer Stoltze.
Evolution does not permit genetic variation
The researchers examined genomes from 140,000 adults who did not have childhood cancer. They examined all the genes in the data that are associated with an increased risk of developing childhood cancer and found little difference between people’s genes worldwide.
Evolution had controlled these genes and not allowed mutations in them. Thus, these genes have not changed appreciably from a common ancestor to you, me and all other humans because of evolutionary pressure.
Of the 85 genes, however, the researchers also found some with considerable variation between people.
This indicates that these genes may not be as relevant to the development of childhood cancer as researchers previously thought. These genes vary too much between adults and within humans as a whole.
“Our studies turn research into the genetic causes of childhood cancer upside down. We know that some genes are associated with increased risk of developing childhood cancer, but we do not need to study children with cancer to find them. We can study genetic differences between people and see where evolutionary pressure has not allowed genetic mutations,” says Ulrik Kristoffer Stoltze.
Investigating other childhood diseases with a genetic component
According to Ulrik Kristoffer Stoltze, the study provides greater insight into the genes that are involved in developing childhood cancer and why evolutionary pressure keeps a firm grip on them.
He sees great potential for similar studies for other diseases and conditions among children, including the genetic predisposition for the development of autism, schizophrenia and stillbirth.
Ultimately, greater insight into the genes of seriously ill children in particular should make screening more precise for children.
Children with genetic variants associated with the risk of childhood cancer may benefit from childhood cancer screening. Today, children are screened in Denmark to determine whether they have an increased risk of developing cancer.
However, according to Ulrik Kristoffer Stoltze, there may be benefits to considering the new knowledge about evolution to determine whether screening is helpful.
“My evolutionary data contribute evidence that, for some of my patients, screening is not helpful. We have to screen many children to determine who has cancer and who does not, and this costs a lot of money and is not without risk to the children and their families. If screenings can be saved, this also forms part of precision medicine or precision prevention,” he adds.
Children with cancer have several mutations
According to Ulrik Kristoffer Stoltze, the study has another perspective.
The new data enabled the researchers to quantify how many people have a genetic variant in the genes that should not have too much variation.
Among the 140,000 people surveyed, 7% had variation in genes that have been under high evolutionary pressure – a fair number. Children who had had childhood cancer had variation in 10% of the relevant genes.
“This is a new way of uncovering the genetic background of childhood disease. First we have to get the theory in place, but this should preferably also lead to a practical and hopefully clinical application,” concludes Ulrik Kristoffer Stoltze.
“The evolutionary impact of childhood cancer on the human gene pool” has been published in Nature Communications. The project was supported by Rigshospitalet’s Research Fund, the Danish Cancer Society, the Danish Childhood Cancer Foundation and the Novo Nordisk Foundation.
