Our bodies are made from millions of cells, and inside every cell there are chromosomes. Chromosomes are made up of DNA that acts like a genetic code, with all the instructions that tell a cell what to do.
Most people have 46 chromosomes in each of their cells, but some people may have more or less than the usual 46 chromosomes.
Down syndrome is a genetic condition that arises during the very first stages of development, when abnormal cell division produces an extra copy of chromosome 21. A change in the number of chromosomes such as this is called aneuploidy.
Down syndrome has been associated with an increased risk of some medical conditions, including heart defects and vision problems. And in 1930, it was discovered that children with Down syndrome are also at a greater risk of developing certain types of leukaemia.
It’s known that children and adolescents with Down syndrome are between 10 to 30 times more likely to develop leukaemia, a cancer of the white blood cells, than those without the condition.
We spoke to Dr David O’Connor, one of our scientists who is a clinical researcher at University College London, and a consultant specialising in childhood blood cancer at Great Ormond Street Hospital, who has previously focussed his work on this link.
Understanding the link
Down syndrome occurs in approximately 1 in every 700 births.
“Down syndrome is a common genetic syndrome,” explains O’Connor. “It’s associated with learning difficulties and various health problems like congenital heart disease. But children with Down syndrome are at significantly increased risk of leukaemia.”
But much of the explanation for why this is the case remains relatively unknown.
What we do know is that there are various types of leukaemia and that the risk of them, and their response to treatment, varies for children with Down syndrome.
1. Acute Myeloid Leukaemia (AML)
Children with Down syndrome are 150 times more likely to develop acute myeloid leukaemia (AML) than children without Down syndrome. The risk of developing a rare subtype of AML, known as acute megakaryoblastic leukemia (AMKL) is increased 500-fold in children with Down syndrome.
O’Connor explains how around 10% of children with Down syndrome have a sort of ‘pre-leukaemia’ at the time of birth, with leukaemia cells visible in the blood.
“So, in a subset of these children, if you look at their blood down the microscope, it will look like acute leukaemia, but we know that in the vast majority of these children, it will go away without any treatment. However, in a proportion of that group, it will come back again later, at about 18 months to 4 years of age. At this stage the children have a true leukaemia and require treatment with intensive chemotherapy.”
2. Acute Lymphoblastic Leukaemia (ALL)
Another type of leukaemia – acute lymphoblastic leukaemia (ALL) – is the most common form of childhood leukaemia, and children with Down syndrome are 20 times more likely to develop this type of cancer than children without Down syndrome.
“Children with Down syndrome are also at increased risk of acute lymphoblastic leukaemia compared to the general population.”
“The Down syndrome diagnosis happened very soon after the birth and it was a shock, but it did not make me love her any less. We had this bond already – she was still mine and that didn’t change.”
Jo is mum to Georgia, a 14-year-old girl who has Down syndrome.
In 2010, when Georgia was just 18 months old, she was diagnosed with AML.
“A couple of months before she was diagnosed, she had a small rash on her ankles which was lots of little dots of blood under the skin,” says Jo. “I had put her in some frilly socks and I didn’t really think it could have been a sign of anything more than an irritation.”
Jo recalls how she had never been told about the higher risk of leukaemia for children with Down syndrome.
“She then got more poorly over the following weeks, including being really lethargic which was very unusual for her – she was always so bubbly. I thought it might have been a cold so I did not act as quickly as I could have.
“I know how important early diagnosis is, and those weeks could have been so important, so I am passionate about raising awareness of this increased risk for children with Down syndrome. Those few weeks could have made all the difference.”
When she was eventually diagnosed, Jo recalls the feeling of being told that Georgia had leukaemia. “The news absolutely floored me and the first thing that came to my mind was, ‘She’s not going to get through this’.
“I always thought that Down syndrome would be the biggest challenge but of all the things we have faced, the cancer diagnosis was the worst. She has also had a form of childhood epilepsy and scoliosis, but the cancer was so tough to understand.”
Variations in treatment response
5-year overall survival for childhood AML in general is around 70% in England. Fortunately, AML in children with Down syndrome is extremely sensitive to the effects of chemotherapy and therefore responds very well to treatment, with trials suggesting a 5-year overall survival of more than 90%.
“With ALL, almost the opposite is true,” says O’Connor. “Their leukaemia is often higher risk and doesn’t respond as well to chemotherapy.” Survival of ALL in children with Down syndrome is slightly lower than what is expected in the wider population.
In addition, as O’Connor explains, children with Down syndrome don’t tend to tolerate chemotherapy very well. “There tends to be a greater risk of side effects, particularly serious infections.” This can make treatment of leukaemia much more challenging.
“Ultimately this is why we want to try to improve treatment efficacy for them, so that we can decrease toxicity and reduce side effects. It’s essentially the same aim for any patient group, but I think it’s particularly important in children with Down syndrome because they have such a high risk of complications.”
Jo explains how Georgia’s treatment was impacted by a weaker immune system. “Because of Down’s she had a weakened immune system, and this would lower it again, so we knew how at risk she might be.”
“The treatment was tough. She was really poorly from a reaction to one treatment and had to go to ICU – they changed the treatment after that and she had a different drug then, but she generally coped with the chemo extremely well.
Jo describes how she was told that while Down Syndrome meant the leukaemia was more likely to develop, if Georgia was to go into remission, she had a higher-than-average-chance of staying in remission.
Research in this area
Research into leukaemia in Down syndrome could significantly improve our understanding about how and why childhood leukaemia develops in children both with and without Down syndrome.
In particular, O’Connor’s PhD focussed on the origins of AML.
Like other types of childhood leukaemia, we know that lots of AML in children starts in utero. “We know that blood development is already abnormal in the fetus. And so we were trying to look at the influence and importance of Trisomy 21, having the extra copy of chromosome 21, and what that does to the blood production in utero.”
But while children with Down syndrome have an extra chromosome 21, that isn’t the only chromosome change connected to leukaemia.
There’s also a phenomenon that we see in children with ALL in which the leukaemia will gain or lose chromosomes.
In a particular type of high risk leukaemia called hypodiploid ALL, children without Down syndrome lose almost half their chromosomes. “But interestingly,” explains O’Connor, “they never lose copies of chromosome 21.”
This again implies that even in ALL, this chromosome plays a significant role in the development of leukaemia.
“There is definitely a research focus to try and understand how leukaemia develops in Down syndrome, in different stages. We know that all leukaemias develop through a multi-step process. In Down syndrome we already know the first step in this process, the gain of a copy of chromosome 21, so this allows us to use leukaemia in Down syndrome as a model to learn more about the development of all leukaemias.”
Despite research making great advances in the treatment and management of leukaemia in children with Down syndrome, much of the science behind the link remains a mystery.
While we know that there is a gene altered on chromosome 21, we don’t know the exact location of the gene responsible.
“There are many excellent researchers working on this at the moment, but it’s probably not one gene working in isolation, it’s a combination, which makes the puzzle harder to solve.”
Georgia and Jo know first-hand the impact research has. “I am in awe of research. Without that, we might not be here to celebrate her 14th birthday. Thanks to research, I still have her here and that means everything.
“If I can help one person spot an early sign of cancer, then it will be worth it.”